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Send Orders of Reprints at reprints@benthamscience.net Current Topics in Medicinal Chemistry, 2013, 13, 1290-1307

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Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs Haizhen A. Zhong*, Victoria Mashinson, Theodor A. Woolman and Mengyi Zha Department of Chemistry, University of Nebraska at Omaha, DSC 362, 6001 Dodge Street, Omaha, NE 68182, USA Abstract: Molecular properties such as the molecular weight, hydrophobicity parameter logP, and the total polar surface area (TPSA) have been used extensively in modern drug discovery. We investigated these properties and ADMET scores of the top 200 therapeutic drugs by the U.S. retail sales (2010) and classified them according to the clinical indications and/or routes of administration. This list of drugs provides ample information of these molecular descriptors for successfully approved drugs. The mean logP for oral drugs is 2.5 while the logP for injectable drugs seems to be smaller. Among different types of clinical indications, drugs used for anti-HIV, and antibiotics tend to have lower logP. The molecular weights of anti-HIV drugs, antihypertensives and antibiotics appear to be larger. The ADMET scores, derived from a combination of molecular weights and logP, are consistent for oral drugs, with a mean score of 1.5 and a standard deviation of 1.0. Many clinical drugs that violate Lipinski’s rule of five criteria can still exhibit ADMET scores that are very close to the mean value for oral drugs (1.5) and lie within the acceptable standard deviation. The molecular properties of MW, logP, and TPSA appear to vary according to their clinical indications. Many drugs form salts or cocrystals with acids or solvents that increase their solubility. Our data show that addition of hydrochloride is the most common method to increase solubility of drug ingredients. Cytochrome P450 isozymes 3A4, 2D6, 2C9, 2C8 and 3C5 are the top five proteins that metabolize the 200 most prescribed drugs. Drugs metabolized by 3A4 appear to have larger molecular weights and those metabolized by 2D6 have lower molecular weights. CYP2C8-metabolized drugs appear to be most hydrophilic, with the smallest logP and the largest polar surface areas.

Keywords: Attrition, anticancer, antihypertensives, antipsychotics, antidiabetes, molecular properties, combinational drugs, salt formation, molecular descriptors and metabolism. INTRODUCTION

(d) the sum of nitrogen and oxygen atoms is greater than 10.

Drug discovery is a high risk enterprise with a prohibitively high attrition rate. Approximately 62% of compounds fail in the Phase II clinical trials. Attrition occurring in full clinical development (Phases IIb and III) can be very expensive. The costs of discovering and developing a drug were approximately US$804 million in 2001 and US$900 million in 2004 [1]. In order to reduce the attrition rate, many physicochemical properties of active molecules or clinical drugs have been studied and generalized with an aim to improve oral bioavailability. Many rules for filtration in the discovery phase have been proposed. Among them the most notable one is Lipinski’s rule-of-five (RO5) [2]. Lipinski and his coworkers proposed that the poor absorption or permeation of a compound is more likely when:

This rule identifies favorable physicochemical properties of most orally active molecules. Lipinskiâ&#x20AC;&#x2122;s RO5 proposed MW and logP as the two most important molecular descriptors for orally bioavailable drugs. Oral bioavailability, however, is not determined by the MW alone. Reduced molecular flexibility, measured by the number of rotatable bonds, and low polar surface area (PSA) were also found to be reliable predictors of good oral bioavailability. The GlaxoSmithKline (GSK) team observed that compounds with (a)  10 rotatable bonds and (b) PSA  140 Ă&#x2026;2 (or  12 H-bond donors and acceptors) have a high probability of good oral bioavailability in rats [3]. Although the GlaxoSmithKline rule does not contain MW, it still has the MW implications. Compounds with MW > 500 tend to have  10 rotatable bonds, along with the observed increased PSA and an increased number of H-bonds. Therefore, molecular properties of MW, logP, and PSA have been used extensively in the drug discovery programs. Leeson and Springthorpe analyzed 592 oral drug approved worldwide between 1983 and 2007 and concluded that the median CLogP for launched drugs in any given year in this period was < 4 and that the median molecular mass (MW) < 450 [4]. The RO5 has been modified to a set of â&#x20AC;&#x153;Traffic Lightsâ&#x20AC;? to address the oral absorption with (a) MW  400, CLogP  3, PSA  120 Ă&#x2026;2 as filters for in silico prioritization of hits [5, 6].

(a) the molecular mass is greater than 500 Dalton; (b) the lipophilicity, measured by the calculated logP (CLogP) is greater than 5; (c) the number of hydrogen-bond donors is greater than 5, and the number of hydrogen-bond acceptors is greater than 10, and

*Address correspondence to this author at the Department of Chemistry, University of Nebraska at Omaha, DSC 362, 6001 Dodge Street, Omaha, NE 68182, U.S.A; Tel: 1-402-554-3145; Fax: 1-402-554-3888 E-mail: hzhong@unomaha.edu /13 $58.00+.00

Š 2013 Bentham Science Publishers


Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

In addition to molecular descriptors, the chirality of the active pharmaceutical ingredients (APIs) are very important as well. Seven out of eleven FDA approved low molecular weight New Molecule Entities (NMEs) in 2010 were chiral. Eighteen drugs with small molecular weights were approved in 2011; half of them had no chiral centers, and the other half were present as enantiopure compounds (Table 1). Some drugs are formulated as the solid ionic salts for the convenient oral route of administration, or formulated into a pill with a combination of two or three drugs. The chirality and formation of salts are as important as the molecular descriptors such as MW, logP, and PSA in evaluating clinical therapeutics. Therefore, it is essential for medicinal chemists to appreciate these properties of the top prescribed clinical drugs. SALES OF TOP THERAPEUTIC CLASSES To investigate the molecular properties of the top sale pharmaceuticals, we downloaded the list of the top 200 pharmaceutical drugs by the U.S. retail sales in 2006 and in 2010 from drugs.com [7]. The original list contains information of rankings (based on sale), drug names, manufacturers, total sales, and percent changes from the previous year. Comparison of drug sales between 2006 and 2010 underscored the shift of therapeutic targets and suggested recent trends in drug development and research. Drug sales in the United States grew by 13.7% from 2006 to 2010, jumping from $270 billion in 2006 to $307 billion in 2010. In terms of different classes of medications, the sales of lipidlowering drugs, anti-ulcerants, erythropoietins, and antiepileptics experienced a decline over this five-year period, while the anticancer drugs, respiratory agents, antipsychotics, anti-ADHD, anti-Alzheimerâ&#x20AC;&#x2122;s, antidiabetics, angiotensin II antagonists, HIV antivirals, and autoimmune regulators enjoyed much gain over the same period (Chart 1). In terms of the percentage growth, drugs targeting ADHD, Alzheimerâ&#x20AC;&#x2122;s disease, multiple sclerosis, diabetes, and HIV ranked in the top five drug classes in the U.S. retail sales, with an 80.0%, 80.0%, 78.1%, 65.7%, and 64.3% increase, respectively. The top four classes of medication in terms of therapeutic sales worldwide are the same as those in the U.S., with anticancer drugs leading the ranks. The top five fastest growing drug classes worldwide are drugs targeting

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autoimmune disease, multiple sclerosis, HIV, angiotensin II antagonists (for hypertension treatment), and diabetes, with 94.8%, 77.9%, 68.2%, 62.3%, and 61.6% of growth, respectively. The increased prescription sales in anticancer, antiAlzheimerâ&#x20AC;&#x2122;s disease, antidiabetics, antihypertensives, and antipsychotics reflect the strong demand from the aging and overweight consumers. The sale statistics also mirrored the extensive research in these fields in recent years. As the largest developed country in the world, the United States in 2010 accounted for approximately 39% of global drug sales ($307 billion in the U.S. out of the global $791 billion). The drug classes with U.S. sales greater than half of global share are narcotic analgesics (69.9%), antipsychotics (63.4%), HIV antivirals (59.6%), antidepressants (57.4%), respiratory agents (53.7%) and lipid regulators (51.6%), and autoimmune agents (51.2%). Americans spent $7.2 billion on ADHD in 2010. The number of worldwide sale of ADHD did not show up in the top 20 drug classes. However, considering the least drug class among the top 20 in term of global sales (multiple sclerosis, $9.8 billion), one can conclude that the U.S. contributed to the majority of ADHD sales in 2010. This is in line with the 80% growth in ADHD sales from 2006 to 2010. By inspecting the share of the U.S. sales (of ADHD, antipsychotics, and antidepressants) in the global market, one can observe an increasing demand in the mental health drugs in the U.S. The reason behind the top sales and the top growth rates in sales of certain drugs could be the research focus on these drug classes in the past two decades, which have witnessed a lot of progress in the anticancer, antidiabetes and the central nervous system (CNS)-related fields. These research areas have been under relentless pursuits by many pharmaceutical companies, in order to find new products from the pipeline to generate new revenues to replace drugs with expiring patent protection. For instance, by the end of 2012, pharmaceutical companies lost patent protection for Lipitor (Pfizer), Zyprexa (Eli Lilly), Seroquel and Nexium (AstraZeneca). The extensive anticancer research in the past decade has helped to bring forth an outpouring of new drug approvals for anticancer drugs in 2011 (ruxolitinib, crizotinib, and vemurafenib) and in 2012 (ponatinib, cabozantinib, regorafenib, bosutinib, axitinib, carfilzomib, and vismodegib).

Chart 1. The top 200 therapeutic sales in U.S.A. (left), and worldwide (right) for the years of 2006 and 2010.


1292 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

Table 1.

Zhong et al.

New Molecular Entity (NME) and New Biologic License Application (BLA) Approvals in 2010 and 2011.

Trade Names

Generic Names

Applicants

Chirality

Indication

Ampyra

Dalfampridine

Acorda Ther. Inc

non-chiral

multiple sclerosis

Lastacaft

Vilasta

Vistakon Pharm. Llc

non-chiral

itching associated with allergic conjunctivitis.

Gilenya

Fingolimod HCl

Novartis

non-chiral

multiple sclerosis

Pradaxa

Dabigatran Etexilate Mesylate

Boehringer Ingelheim

non-chiral

stroke and systemic embolism

Carbaglu

Carglumic Acid

Orphan Europe

chiral

acute and chronic hyperammonemia

Jevtana

Cabazitaxel

Sanofi Aventis

chiral

metastatic prostate cancer

Ella

Ulipristal Acetate

Lab. Hra Pharma

chiral

prevention of pregnan

Latuda

Lurasidone HCl

Sunovion Pharm. Inc

chiral

schizophrenia in adults

Teflaro

Ceftaroline Fosamil For Injection

Cerexa Inc

chiral

acute bacterial skin infections and community acquired pneumonia

Halaven

Eribulin Mesylate

Eisai Inc

chiral

metastatic breast cancer

Natazia

Estradial Valerate/Dienogest Tabs

Bayer

chiral

prevention of pregnancy

Caprelsa

Vandetanib

AstraZeneca

non-chiral

thyroid cancer

Edarbi

Azilsartan medoxomil

Takeda

non-chiral

hypertension

Edurant

Rilpivirine

Gilead

non-chiral

HIV

Ferriprox

Deferiprone

Apotex

non-chiral

transfusional iron overload

Horizant

Gabapentin enacarbil

GlaxoSmithKline

non-chiral

restless legs syndrome

Onfi

Clobazam

Lundbeck

non-chiral

seizures

Potiga

Ezogabine

Valeant Pharma

non-chiral

seizures

Viibryd

Vilazodone hydrochloride

Clinical Data

non-chiral

major depression

Zelboraf

Vemurafenib

Roche

non-chiral

BRAF + melanoma

Brilinta

Ticagrelor

AstraZeneca

chiral

acute coronary syndrome (stroke, heart attack)

Dificid

Fidaxomicin

Optimer Pharma

chiral

diarrhea

Incivek

Telaprevir

Vertex

chiral

chronic hepatitis C

Jakafi

Ruxolitinib

Incyte

chiral

myelofibrosis

Tradjenta

Linagliptin

Boehringer Ingelheim

chiral

type II diabetes

Victrelis

Boceprevir

Merck

chiral

chronic hepatitis C

Xalkori

Crizotinib

Pfizer

chiral

ALK+ non-small cell lung cancer

Xarelto

Rivaroxaban

Janssen Pharma

chiral

stroke

Zytiga

Abiraterone acetate

Centocor Ortho Biotech

chiral

prostate cancer

2010

2011

MOLECULAR PROPERTIES OF TOP THERAPEUTICS After the top 200 therapeutic drugs were downloaded, we classified these drugs according to their therapeutic use. The generic names, clinical indications, and mechanism of action

of these drugs were collected based on the DrugBank database [8], the metabolisms of each drug were recorded based on the SuperCyp database [9], and the route of administration information was obtained from the FDA Approved Drug Products database [10]. The three dimensional structures of


Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

these low molecular weight drugs were built and minimized using the MOE program [11]. The molecular properties of molecular weight (MW), hydrophobic parameter (logP), and the topological polar surface area (TPSA) of these drugs were calculated using the MOE program. Table 2 lists these molecular properties, route of administration, and the mechanism of action (MOA) of each of low MW drugs. The structures of the human monoclonal antibodies (mAb) and polypeptide drugs, were excluded from Table 2 due to their large molecular weights. Drugs in Table 2 are grouped by therapeutic indications and ranked according to the top therapeutic classes shown in Chart 1. Within the same class, drugs are ranked based on increasing logP values. To save table space, the mechanism of action (MOA) for the major group of drugs is given in () following the classification of indications. Only drugs having a different MOA are denoted, otherwise, the drugs have the same MOA as indicated in the parenthesis. Table 2 shows that the majority of the top 200 therapeutic drugs either target enzymes as inhibitors, or bind to receptors as agonists or antagonists. This observation is in good agreement with Hopkins and Groom’s finding that approximately 47% of small molecule drugs target enzymes and 30% target G-protein coupled receptors (GPCRs) [12]. Histamine receptors (H receptors), mAChR, the various  and  subtypes of adrenergic receptors, and opioid receptors listed in Table 2 all belong to the GPCR family. There are still quite a few drugs whose exact mechanism of action remains elusive. Without exception, all central nervous system (CNS)-acting drugs, including antipsychotics, antidepressants, anti-ADHD, anti-epileptics, anti-Alzheimer’s, antiinsomnia, anti-narcolepsy, and anti-Parkinson’s, show molecular weight less than 500, in accordance with the Lipinski’s RO5. With the exception of sertraline (logP of 5.5), the calculated hydrophobicity as measured by logP for all other CNS drugs is < 5. The TPSA of all CNS acting drugs range from 9 to 116 Å2, below the GSK’s rule of TPSA < 140 Å2 for good oral bioavailability. Non-steroid-based drugs for the treatment of allergy, asthma, and chronic obstructive pulmonary disease (COPD) also abide by the Lipinski’s RO5 and GSK’s rule on TPSA, though most of these anti-allergic, anti COPD and anti-asthma drugs were administered via nasal or inhalation routes. Other drugs satisfying the RO5 and GSK observations include hormonal contraceptives, drugs against diabetes, erectile dysfunction, glaucoma, overactive bladder and hormone replacement therapy. The studies of route of administration of top pharmaceuticals show that oral drugs account for 78%, followed by injectable drugs, inhalable and ocular drugs. The mean logP for oral drugs is 2.51, whereas injectable drugs are more polar with less hydrophobic logP and larger TPSA, suggesting that injectable compounds are more polar (Table 3). The average values of MW, logP, and TPSA along with the standard deviations for oral drugs with common clinical indications are listed in Table 4. For instance, the average MW (with the standard deviations) for the CNS-acting drugs is 289 ± 76, with an average logP of 2.5 ± 1.4, and an average TPSA of 49.9 ± 22.6 Å2. Drugs targeting HIV, bacteria/fungi, and hypertension in general show higher MW. Surprisingly, the most hydrophobic drugs are not the CNS-

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acting drugs. Rather, they are the anti-asthma drugs (mean logP: 3.9) and antihypertensives (3.6). The anti-HIV, and antibiotics appear to be the least hydrophobic with the mean logP close to 1. These two classes of drugs on average tend to be the most hydrophilic with the largest TPSA, followed by antihypertensives and anticancer drugs. It has to be pointed out that the average values of these molecular properties may be slightly different if a much larger database including all the FDA-approved drugs is used for analysis. Such a database would contain thousands of clinical drugs and is beyond the scope of this study. Please note that the molecular properties listed in Table 4 only reflect those oral drugs with the exclusion of injectable and inhalable drugs. A study by Walters et al. on compounds published in the Journal of Medicinal Chemistry over the past century showed that mean value for molecular weight increased from ~300 to 388 Daltons in 1959-2009, with TPSA increasing from ~ 60 to ~80 Å2 [13]. The molecular weights and TPSAs observed in anticancer, anti-HIV, antihypertensives, and antibiotics were very close to those observed by Walters [13]. A comparison of drugs before and after 1980 revealed that the molecular weights increased from 309 to 385 Daltons and calculated logP stayed constant at ~2.6 [14]. The molecular weights of oral drugs were consistent across literature. However, Table 4 suggests that the hydrophobic parameter logP might be dependent upon the clinical indications of oral drugs, with the antihypertensives showing the largest mean logP. It is noted that not all drugs follow the RO5 and GSK’s TPSA rule. Most drugs in the family of lipid regulators, oral anticancer, antibiotics, HIV-antivirals, and antihypertensives satisfy RO5 and/or GSK’s TPSA rule. However, some exceptions do occur. For instance, some antivirals and antibiotics tend to have larger MW. Most of those molecules that violate one or more of RO5 and/or GSK’s TPSA rule, after careful inspection, can be classified into two categories: either (a) they are administered via injection which makes the oral bioavailability issue less relevant, or (b) they are able to form a salt to enhance their solubility. For instance, the high molecular weight anticancer drugs taxotere (MW: 807.9), and paclitaxel (MW: 853.9), and the antibiotics azithromycin (MW: 749.0) are administered via injection, and the high molecular weight atorvastatin is administered as calcium salts. The RO5 specifies the relationship between poor absorption and MW, logP and other molecular descriptors. However, it does not involve other aspects of ADMET properties such as distribution, metabolism and solubility. Many reports have related the ADMET parameters with MW and logP [15, 16]. A simple ADMET score was proposed to correlate the oral-drug space with molecular weight and hydrophobicity parameter logP [17]. This score was calculated by using the means and standard deviations of MW and logP of available oral drugs. This score is particularly relevant since the properties of successful oral drugs were used to obtain such a score. In this paper, we define the ADMET score as a function of MW and logP (Eq. 1). ADMET score= | log Pmean  log P | + | MWmean  MW | (Eq. 1) log PSD MWSD


1294 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

Table 2.

Zhong et al.

Molecular Properties of Top 200 Prescribed Drugs.

Drugs (MOA)

Route

MW

logP

TPSA

Drugs (MOA)

Route

MW

logP

TPSA

Antineoplastics (DNA alkylator, a1; NNRTI, a2; aromatase inhibitor, a3; angiogenesis inhibitor, a4, EGFR inhibitor, a5)

Respiratory Agents

Temozolomide (a1)

Oral

194.2

-2.7

105.9

Allergy (Antihistamines, H1 receptor antagonists)

Gemcitabine (a2)

Injectable

264.2

-0.9

110.0

Desloratadine

Oral

310.8

3.4

24.9

Lenalidomide (a4)

Oral

259.3

-0.2

92.5

Levocetirizine

Oral

388.9

3.5

57.0

Thalidomide (a4)

Oral

258.2

0.4

83.6

Loratadine

Oral

384.9

3.6

41.6

Oxaliplatin (a1)

Injectable

397.3

0.6

85.8

Olopatadine

Ocular

337.4

4.0

49.8

Capecitabine (a2)

Oral

359.4

0.8

120.7

Azelastine

Nasal, Ocular

381.9

5.2

35.9

Pemetrexed (TS and DHFR inhibitor)

Injectable

425.4

1.3

192.6

Fexofenadine

Oral

502.7

7.3

82.2

Letrozole (a3)

Oral

285.3

2.0

78.3

Asthma (Adrenergic bronchodilators, 2 agonist)

Erlotinib (a5)

Oral

393.4

2.3

74.7

Epinephrine

Inhalation

183.2

0.5

72.7

Bicalutamide (androgen receptor inhibitor)

Oral

430.4

2.5

107.3

Levalbuterol

Inhalation

240.3

1.5

77.3

Imatinib (Bcr-abl inhibitor)

Oral

494.6

2.8

87.5

Formoterol

Inhalation

345.4

2.4

95.4

Anastrozole (a3)

Oral

293.4

3.2

78.3

Salmeterol

Inhalation

415.6

4.8

82.0

Taxotere (microtubulin stabilizer)

Injectable

807.9

3.6

224.5

Chronic Obstructive Pulmonary Disease (COPD) (mAChR antagonists)

Paclitaxel (microtubulin stabilizer)

Injectable

853.9

4.3

221.3

Tiotropium

Inhalation

392.5

2.1

59.1

Irinotecan (topoisomerase I inhibitor)

Injectable

587.7

4.4

113.7

Ipratropium

Inhalation

331.5

2.4

46.5

Raloxifene (SERMs)

Oral

474.6

6.6

71.2

Asthma (Inhaled corticosteroids) (glucocorticoid receptor agonists)

Cinacalcet (calciumsensing receptor agonist)

Oral

357.4

6.7

12.0

Triamcinolone Acetonide

Injectable

434.5

3.1

93.1

Fluticasone Propionate

Topical

500.6

4.7

171.2

Fluticasone Furoate

Nasal

525.6

4.8

80.7

Topical

521.4

4.8

93.8

Lipid regulators (HMG-CoA reductase inhibitors) Niacin (triglyceride synthesis inhibitor)

Oral

123.1

0.4

50.2

Mometasone

Rosuvastatin

Oral

480.5

1.6

143.8

Asthma (Leukotriene modifiers, leukotriene receptor antagonists)

Pravastatin

Oral

423.5

2.6

127.1

Montelukast

Fluvastatin

Oral

410.5

4.4

85.5

Simvastatin

Oral

418.6

4.4

72.8

Antipsychotics (Schizophrenia) (D2 /5-HT2A receptor antagonists)

Ezetimibe (cholesterol absorption inhibitor)

Oral

409.4

4.9

60.8

Paliperidone

Oral

426.5

2.1

82.2

Fenofibrate (PPAR- activator)

Oral

360.8

5.2

52.6

Olanzapine

Oral

312.4

2.4

30.9

Atorvastatin

Oral

557.6

5.8

114.6

Quetiapine

Oral

383.5

2.5

48.3

Oral

585.2

9.3

73.3


Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

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1295

(Table 2) contdâ&#x20AC;Ś.

Drugs (MOA)

Route

MW

logP

TPSA

Antidiabetes (Depeptidyl peptidase-4 inhibitors)

Drugs (MOA)

Route

MW

logP

TPSA

Risperidone

Oral

411.5

3.3

63.6

Metformin

Oral

130.2

-0.3

90.7

Ziprasidone

Oral

414.0

3.9

49.7

Sitagliptin

Oral

408.3

2.5

75.5

Aripiprazole (D2/5-HT1A partial agonist)

Oral

448.4

4.9

44.8

Rosiglitazone (PPAR agonist)

Oral

357.4

2.6

71.5

Antidepressants (SSNRI)

Glimepiride (unknown)

Oral

490.6

2.9

124.7

Desvenlafaxine

Oral

263.4

2.9

43.7

Pioglitazone (PPAR agonist)

Oral

356.5

3.3

68.3

Venlafaxine

Oral

278.4

3.2

33.9

Repaglinide (K+ channel blocker)

Oral

452.6

5.9

78.9

Paroxetine (SSRI)

Oral

329.4

3.4

39.7

Bupropion (SSRI)

Oral

240.8

3.5

33.7

Escitalopram

Oral

324.4

4.4

36.3

Anti-Ulcerants (H+/K+ ATPase inhibitors) Esomeprazole

Oral

344.4

0.9

80.5

Duloxetine

Oral

298.4

4.6

25.9

Omeprazole

Oral

345.4

1.3

96.3

Sertraline (SSRI)

Oral

307.2

5.5

16.6

Pantoprazole

Injectable

382.4

0.6

89.8

Anti-ADHD (dopamine reuptake inhibitors)

Lansoprazole

Oral

369.4

1.8

87.1

Lisdexamfetamine

Oral

263.4

1.4

81.1

Famotidine (H2 antagonist)

Oral

337.5

-0.9

175.8

Amphetamine

Oral

136.2

1.7

27.6

Ranitidine (H2 antagonist)

Oral

315.4

0.9

87.5

Dexmethylphenidate

Oral

233.3

2.5

38.3

Rabeprazole

Oral

357.5

2.0

67.6

Methylphenidate

Oral

233.3

2.5

38.3

Mesalamine (unknown)

Rectal

153.1

0.6

83.6

Atomoxetine

Oral

256.4

4.1

25.8

Anti-Epileptics (Na + channel blocker) HIV Antivirals (HIV-1 protease inhibitors, b1; HIV-1 NRTI, b2; HIV1 integrase inhibitor, b3; NNRTI, b4)

Levetiracetam (SV2A stimulator)

Oral

170.2

-0.4

63.4

Tenofovir (b2)

Oral

287.2

-2.6

136.4

Gabapentin (Ca2+ channel blocker)

Oral

171.2

1.1

67.8

Zidovudine (b2)

Oral

267.3

-2.1

103.6

Pregabalin (Ca2+ channel blocker)

Oral

158.2

1.1

66.2

Lamivudine (b2)

Oral

229.3

-0.8

88.2

Topiramate

Oral

339.4

1.5

115.5

Abacavir (b2)

Oral

286.3

-0.6

101.9

Oxcarbazepine

Oral

252.3

2.0

63.4

Emtricitabine (b2)

Oral

247.3

-0.5

88.2

Lamotrigine

Oral

256.1

2.5

90.7

Raltegravir (b3)

Oral

444.4

0.8

150.0

Sodium valproate

Injectable

143.2

2.7

40.1

Darunavir (b1)

Oral

547.7

3.0

140.4

Anti-Alzheimer's (AChE inhibitors)

Ritonavir (b1)

Oral

722.0

3.8

145.3

Rivastigmine

Oral

251.4

2.6

34.0

Efavirenz (b4)

Oral

315.7

4.1

38.3

Oral

180.3

2.8

27.6

Memantine (NMDA receptor inhibitor)


1296 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

Zhong et al.

(Table 2) contdâ&#x20AC;Ś.

Drugs (MOA)

Route

MW

logP

TPSA

Drugs (MOA)

Route

MW

logP

TPSA

Atazanavir (b1)

Oral

704.9

4.7

171.2

Donepezil

Oral

379.5

4.2

38.8

Lopinavir (b1)

Oral

628.8

5.2

120.0

Other CNS Drugs

Inhalation

200.1

2.1

9.2

Injectable; Topical

234.3

2.2

32.3

HSV Antivirals (HSV thymidine kinase inhibitors) Acyclovir

Oral

225.2

Anesthetics (NMDA receptor antagonists) -2.6

114.8

Sevoflurane +

Valaciclovir

Oral

325.4

-1.8

148.5

Influenza Antivirals (Influenza virus neuraminidase inhibitors) Oseltamivir

Oral

312.4

1.4

Lidocaine (Na channel blocker)

Anti-Insomnia (GABA A receptor agonists) 90.7

Antihypertensives (Angiotensin II receptor antagonists)

Zolpidem

Oral

307.4

2.7

35.9

Eszopiclone

Oral

388.8

-0.3

91.8

273.4

1.3

79.4

Narcolepsy (excessive sleepiness)

Losartan

Oral

421.9

4.3

76.7

Modafinil

Olmesartan

Oral

559.6

4.5

145.1

Anti-Parkinson's (D 2 agonists)

Valsartan

Oral

435.5

5.2

112.1

Pramipexole

Oral

211.3

1.4

50.9

Irbesartan

Oral

428.5

5.4

87.1

Ropinirole

Oral

261.4

3.0

33.5

Candesartan

Oral

441.5

5.4

121.9

Telmisartan

Oral

514.6

6.6

72.9

Antihypertensives (ACE inhibitors)

Oral

Narcotic Analgesics ( opioid receptor agonists) Oxymorphone

Oral

301.3

0.2

70.0

Enalapril

Oral

377.5

2.4

100.5

Oxycodone (k opioid receptor agonist)

Oral

315.4

0.8

59.0

Ramipril

Oral

416.5

3.3

95.9

Morphine

Oral

285.3

0.9

52.9

Benazepril

Oral

424.5

3.4

95.9

Hydrocodone

Oral

299.4

1.6

38.8

Tramadol

Oral

263.4

3.1

32.7

Fentanyl

Oral

336.5

4.3

23.6

Antihyertensives (Ca 2+ channel blocker) Doxazosin (1 blocker)

Oral

451.5

1.0

112.3

Metoprolol (1 blocker)

Oral

268.4

1.9

55.3

Opioid overdose ( opioid receptor antagonists)

Amlodipine

Oral

409.9

2.4

101.5

Naloxone

Injectable

327.9

1.2

70.0

Clonidine (2 agonist)

Oral

230.1

2.4

36.4

Buprenorphine ( opioid receptor partial agonist)

Injectable

467.7

4.8

62.2

Nifedipine

Oral

346.3

2.5

110.5

Non-Narcotic Analgesics (COX-2 inhibitors)

Congestive Heart Failure (-/1 blocker) Carvedilol

Oral

406.5

4.0

75.7

Pulmonary Artery Hypertension (Endothelin-1 antagonists)

Meloxicam

Oral

351.4

0.9

99.6

Diclofenac

Oral

295.1

4.3

52.2

NSAID (arthritis) (COX-2 inhibitors)

Bosentan

Oral

551.6

3.4

145.7

Celecoxib

Oral

382.4

3.3

77.0

Cilastatin (dehydropeptidase inhibitor)

Injectable

358.5

-1.3

129.7

Rizatriptan

Oral

269.4

1.1

49.7


Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

1297

(Table 2) contdâ&#x20AC;Ś.

Drugs (MOA)

Route

MW

logP

TPSA

Drugs (MOA)

Route

MW

logP

TPSA

Antibiotics (Bacterial cell wall synthesis inhibitors, c1; bacterial protein synthesis inhibitors, c2; topoisomerase II/IV inhibitors, c3; -lactamase, c4)

Pain (migraine) (5-HT1B/1D receptor agonists)

Tazobactam (c4)

Injectable

313.3

-1.1

125.3

Sumatriptan

Oral

296.4

1.7

66.4

Clavulanate (c4)

Oral

198.2

-1.1

89.9

Eletriptan

Oral

382.5

4.2

53.2

Doxycycline (c2)

Injectable

444.4

-0.8

181.6

Osteoporosis (Farnesyl pyrophosphate (FPP) synthase inhibitors)

Meropenem (c1)

Injectable

383.5

-0.6

110.2

Zoledronic acid

Injectable

272.1

-4.6

153.1

Imipenem (c1)

Injectable

300.4

-0.6

118.3

Alendronate

Oral

249.1

-3.4

161.3

Cefdinir (c1)

Oral

395.4

-0.3

158.2

Ibandronate

Oral

319.2

-1.2

138.5

Piperacillin (c1)

Injectable

516.6

0.0

159.3

Risedronate (inhibit Osteoclast activity)

Oral

282.1

-2.8

145.0

Linezolid (c2)

Oral

337.4

0.4

71.1

Amoxicillin (c1)

Oral

365.4

0.4

133.0

Hormonal Contraceptives (Progesterone receptor antagonists)

Levofloxacin (c3)

Oral

361.4

0.5

73.3

Estrogestrel (Estrogen receptor agonist)

Vaginal

324.5

3.0

37.3

Ciprofloxacin (c3)

Oral

332.4

0.9

77.5

Norgestimate (sperm penetration inhibitor)

Oral

369.5

4.4

58.9

Moxifloxacin (c3)

Oral

402.5

1.8

86.7

Drospirenone

Oral

366.5

3.38

43.4

Clarithromycin (c2)

Oral

749.0

3.1

184.1

Norethindrone

Oral

340.5

3.7

43.4

Azithromycin (c2)

Oral

749.0

3.4

181.1

Ethinyl Estradiol (Estrogen receptor agonist)

Oral

296.4

4.2

40.5

Anti-Bacterials (retinoic acid nuclear receptor agonist)

Antiplatelet Aggregation

Adapalene

Topical

412.5

7.3

46.5

Dipyridamole (adenosine uptake inhibitor)

Oral

504.6

-0.2

145.4

Clindamycin (bacterial protein synthesis inhibitor)

Oral

425.0

1.1

102.3

Aspirin (COX-1/2 inhibitors)

Oral

180.2

1.5

63.6

Clopidogrel (platelet aggregation inhibitor)

Oral

322.8

3.7

30.7

Anti-Fungals (Sterol 14 sterol demethylase inhibitors)

Erectile dysfunction (cGMP specific phosphodiesterase-5 inhibitors)

Voriconazole

Oral

349.3

0.6

76.7

Sildenafil

Oral

475.6

0.5

110.3

Fluconazole

Oral

306.3

-0.7

81.7

Vardenafil

Oral

489.6

1.0

110.3

Terbinafine (squaline monooxygen-ase inhibitor)

Oral

291.4

5.9

3.2

Tadalafil

Oral

389.4

2.3

74.87

Miscellanious Drug Benign prostatic hyperplasia (1-blocker)

Glaucoma (prostanoid receptor agonists)

Alfuzosin

Oral

389.5

0.9

111.8

Dorzolamide (carbonic anhydrase inhibitor)

Ocular

325.5

0.6

110.9

Tamsulosin

Oral

409.5

2.3

104.5

Brimonidine (2 agonist)

Ocular

292.1

1.4

62.2

Dutasteride (5 reductase inhibitor)

Oral

528.5

5.9

58.2

Bimatoprost

Ocular

415.6

2.7

89.8


1298 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

Zhong et al.

(Table 2) contd….

Drugs (MOA)

Route

MW

logP

TPSA

Constipation (CIC-2 chloride channels activator) Lubiprostone

Oral

390.5

5.2

83.8

Drugs (MOA)

Route

MW

logP

TPSA

Travoprost

Ocular

500.6

4.0

96.2

Latanoprost

Ocular

432.6

4.4

87.0

Hair loss (men only) (Steroid type II 5 reductase inhibitors) Finasteride

Oral

372.6

3.6

58.2 Hormone replacement therapy (SERM, Selective estrogen receptor modulators)

Hypothyroidism (synthetic thyroid hormone) Levothyroxine

Oral

775.9

7.2

95.6

Muscle spasms (unknown) Metaxalone

Oral

Estrone

Injestable

270.4

3.2

37.3

Estradiol

Transdermal; Oral

272.4

3.9

40.5

Injectable

288.4

3.1

37.3

221.3

1.9

47.6

Testosterone

495.8

8.9

81.7

Overactive bladder (mAChR antagonists)

Obesity (pancreatic lipase inhibitors) Orlistat

Oral

Psoriasis (unknown) Calcipotriene

Topical

Betamethasone

Topical

504.6

4.3

107.0

Solifenacin

Oral

362.5

4.6

32.8

Tolterodine

Oral

326.5

5.76

24.7

Darifenacin

Oral

426.6

5.1

55.6

Smoking addiction (nAChR partial agonist) Varenicline

Oral

211.3

0.9

37.8

Antienemics (nausea/vomiting, 5-HT3 receptor antagonists) Ondansetron

Oral

294.4

3.3

41.1

Immunosuppressive (Inosine monophosphate dehydrogenase inhibitors ) Tacrolimus (IL-2 production inhibitor)

Oral

804.0

4.6

178.4

Mycophenolate

Oral

433.5

1.94

94.5

Note: NNRTI, Non-nucleoside reverse-transcriptase inhibitor; EGFR, Epidermal growth factor receptor; PPAR, Peroxisome proliferator-activated receptor; NRTI, Nucleoside analog reverse-transcriptase inhibitor; HSV, Herpes simplex virus; ACE, angiotensin-converting enzyme; nAChR, Nicotinic acetylcholine receptor; mAChR, Muscarinic acetylcholine receptor; 5-HT; 5-Hydroxytryptamine (or Serotonin); SSRI, Selective serotonin reuptake inhibitor; SSNRI, SSNRI, Selective serotonin norepinephrine reuptake inhibitor; SV2A, Synaptic vesicle glycoprotein 2A; NMDA, N-Methyl-D-aspartate; GABA, -Aminobutyric acid; COX-2, Prostaglandin-endoperoxide synthase 2 (also known as cyclooxygenase-2); cGMP, Cyclic guanosine monophosphate; and IL-2, Interleukin 2.

Table 3.

Molecular Properties of Pharmaceuticals Based on Different Route of Administration.

Classes

Count

Percentile

MW

logP

TPSA (Å2)

Oral

152

78.4

362.9

2.5

79.7

Injectable

21

10.8

403.5

1.2

113.7

Inhalable/Nasal

8

4.1

301.2

2.3

63.2

Ocular

7

3.6

383.7

3.2

76.0

Table 4.

The Average Values (With the Standard Deviations) of Molecular Properties of the Top Therapeutic Drugs Classified by Common Clinical Indications (Orals).

Classes

Anti-CNS

Anticancer

Anti-HIV

Antihypertensives

Antibiotics/antifungals

MW

289 (76)

345 (96)

409 (192)

409 (85)

405 (163)

2.5 (1.4)

2.2 (2.8)

1.1 (3.0)

3.6 (1.6)

1.2 (1.9)

49.9 (22.6)

82.9 (28.2)

116.5 (35.7)

94.6 (27.8)

101.4 (50.4)

logP 2

TPSA (Å )


Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

Table 5.

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

1299

The Mean Values (With the Standard Deviations) of Molecular Properties and ADMET Scores of the Top Therapeutic Drugs vs. Compounds From Other Sources.

Classes

Oral Drugs (N = 152)

Injectable Drugs (N = 21)

Oral Drugs (N = 1,791)a

ChEMBL (All) (N = 201,355)a

ChEMBL (1 nM) (N = 15, 934)a

MW

363(125)

403 (175)

333 (316)

430 (418)

490 (475)

logP

2.5 (3)

1.2 (2.4)

2.5 (2.0)

3.5 (2.1)

4.0 (2.0)

ADMET Score

1.5 (1.0)

1.5 (1.0)

1.2 (1.0)

1.9 (1.4)

2.4 (1.5)

Note: a) these data were abstracted from Reference 17.

In equation 1, logPmean is the mean value of logP of a given population, for instance 152 oral drugs among the top 200 most prescribed drugs, logP, an individual number of a given drug, logPSD, the standard deviation of logP of this population. The same concept applies to MW. Table 5 shows that mean logP of 152 oral drugs in this study is almost identical to oral drugs from a much larger population (1,791). Compounds from the comprehensive ChEMBL database possess larger logP (3.5 or 4.0). ChEMBL database is a publicly available database of drugs, drug-like small molecules that are compiled and maintained by the European Bioinformatics Institute (EBI), part of the European Molecular Biology Laboratory (EMBL). In addition to increasing logP, compounds in ChEMBL have larger MW, and larger ADMET scores as well (Table 5). This ADMET score, derived from a combination of both MW and logP, is particularly useful for compounds that violate the MW and/or logP rule of RO5. Compounds with MW > 500, or logP > 5 would have been filtered out for further research should only the RO5 be used as a filter in the discovery phase. The mean ADMET score (1.5) for 152 oral drugs in our study is close to that of 1,791 oral drugs. The drugs and drug-like molecules in ChEMBL again show larger numbers. It is surprising to observe that injectable drugs (1.5) have identical ADMET scores of oral drugs (1.5, Table 5). Gleeson et al. observed that 12% of oral drugs, 14% of the ChEMBL compounds, and 21% of the nanomolar potency ChEMBL molecules violate two or more RO5 criteria [17]. Table 6 list top drugs that fail to follow RO5 criteria in that they have either MW > 500, or logP > 5, or both. However, if the ADMET score is used as a filter, most of them will fall within one standard deviation of the mean value (1.5 Âą 1.0). Only two drugs (levothyroxine and montelukast) have ADMET scores above two standard deviations of the mean ADMET score. Herein the advantage of using ADMET score as a filter in drug discovery is evident. FORMATION OF IONIC SALTS Approaches to enhancing solubility of APIs include the utilization of ionic salts with sodium, calcium, potassium, or with hydrochloride, citrate, tartrate or other acids. In addition to the formation of salts, cocrystalization with solvents such as ethanol or with water (becoming hydrates) can change molecular properties as well. Table 7 shows the occurrence of various salts or cocrystals of solvents among the top 200 therapeutic drugs. Addition of HCl to APIs appears to be the most common, accounting for 42.7% of all forms of anionic

salts. This is not surprising as it is shown that 39% of oral drugs are present in bases, 35% in neutrals, 17% in acids, 6% in zwitterions, and 3% in cations [18]. Other acids being used in formulation of APIs include sulfate, fumarate, tartrate, phosphate, succinate, besylate, citrate, maleate, and mesylate. The addition of acids such as hydrochloride and fumarate to APIs not only renders the formation of salts, but also assists the formation of crystalline lattice via network of hydrogen bonds mediated through the acids [19]. Among the top 200 pharmaceuticals, 15 drugs exist as sodium, calcium, potassium, and magnesium. Among these cationic salts, formation of sodium salts is the most popular, followed by calcium and potassium. Berge et al. observed that 43.0% of FDA approved drugs (through 1974) were marketed as hydrochloride, followed by sulfate (7.5%) and that sodium as the most frequently used cation, followed by magnesium and calcium [20]. The trend observed in the most recent drugs in terms of the population of drugs forming cationic and/or anionic salts was similar to those approved four decades ago. COMBINATION THERAPY OF TOP DRUGS By comparing the generic names and the brand names of top drugs, one can conclude that there are a number of drugs prescribed in combination. By inspecting the mechanisms of action of these combination drugs (Table 8), one can propose that most combinational drugs target different pathways to maximize the therapeutic outcome. For instance, antihypertensive drugs Avalide, Benicar HCT, Diovan HCT, and Micardis HCT represent four different angiotensin II receptor antagonists in combination with a common hydrochlorothiazide (HCT) as a diuretic to inhibit the kidneyâ&#x20AC;&#x2122;s ability to retain water, thus reducing the volume of the blood and lowering peripheral vascular resistance. Other approaches to reducing high blood pressure are demonstrated in Exforge by combining an angiotensin II receptor antagonist and a Ca2+ channel blocker; or in Lotrel by adding a Ca2+ channel blocker to an ACE inhibitor. These complementary combinations can be found in Vytorin, which is a combination of ezetimibe and simvastatin. Ezetimibe (Zetia) reduces blood cholesterol level by inhibiting cholesterol absorption, while simvastatin inhibits HMG-CoA reductase, an enzyme critical for cholesterol synthesis. By interrupting both cholesterol absorption and cholesterol synthesis, Vytorin can effectively decrease blood cholesterol level. Other examples follow the same complementary pattern. Therefore, when developing a single pill with two or more APIs, it is important to keep in mind that it is better to combine drugs with com-


1300 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

Table 6.

Zhong et al.

The ADMET Scores and Molecular Properties of the Top Drugs that Violate One or More RO5 Rules.

Drugs

Route

MW

logP

TPSA

ADMET Score

Atorvastatin

Oral

557.6

5.8

114.6

3.0

Bosentan

Oral

551.6

3.4

145.7

1.9

Candesartan

Oral

441.5

5.4

121.9

1.9

Cinacalcet

Oral

357.4

6.7

12.0

1.9

Darunavir

Oral

547.7

3.0

140.4

1.9

Dipyridamole

Oral

504.6

-0.2

145.4

2.3

Dutasteride

Oral

528.5

5.9

58.2

2.8

Fexofenadine

Oral

502.7

7.3

82.2

3.2

Irbesartan

Oral

428.5

5.4

87.1

1.8

Levothyroxine

Oral

775.9

7.2

95.6

5.4

Lubiprostone

Oral

390.5

5.2

83.8

1.4

Montelukast

Oral

585.2

9.3

73.3

4.8

Olmesartan

Oral

559.6

4.5

145.1

2.4

Repaglinide

Oral

452.6

5.9

78.9

2.2

Sertraline

Oral

307.2

5.5

16.6

1.7

Telmisartan

Oral

514.6

6.6

72.9

3.0

Table 7.

Number and the Percentage of Occurrence (%Occ.) of Salts and Solvents Among the Top 200 Therapeutic Drugs.

Na+

Name

Ca2+

K+

Mg2+

Number

8

3

3

1

Percent

10.7

4.0

4.0

1.3

Name

HCl

H2SO 4

fumarate

tartrate

phosphate

succinate

besylate

HBr

Number

32

9

6

5

4

4

3

3

Percent

42.7

12.0

8.0

6.7

5.3

5.3

4.0

4.0

Name

maleate

mesylate

citrate

acetate

ethanol

benzoate

oxalate

xinafoate

Number

2

2

2

1

1

1

1

1

Precent

2.7

2.7

2.7

1.3

1.3

1.3

1.3

1.3

Table 8.

The Mechanisms of Action (MOA) of the Combinational Drugs.

Brand Names

Generic Names

MOA

Brand Names

Generic Names

MOA

Avalide

Irbesartan

angiotensin II receptor antagonist

Janumet

Sitagliptin

DDP-4 inhibitor

Hydrochlorothiazide

diuretic

Metformin HCl

Glucose level regulator

Actoplus Met

Pioglitazone

PPAR agonist

Lopinavir

HIV-1 protease inhibitor



Metformin

DPP 4 inhibitor

Ritonavir

HIV-1 protease inhibitor

Kaletra


Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

1301

(Table 8) contdâ&#x20AC;Ś. Brand Names

Generic Names

MOA

Brand Names

Generic Names

MOA

Advair Diskus

Fluticasone

-agonist

Loestrin 24 Fe

Norethindrone Acetate

Progesterone receptor antagonist

Salmeterol

2 agonist

Ethinyl Estradiol

Androgen antagonist

Aspirin

COX inhibitor

Amlodipine

Ca2+ channel blocker

Dipyridamole

adenosine uptake inhibitor

Benazepril

ACE inhibitor

Efavirenz

HIV-1 NNRTI

Telmisartan

angiotensin II receptor antagonist

Emtricitabine

HIV-1 NRTI

Hydrochlorothiazide

diuretic

Tenofovir Disoproxil Fumarate

HIV-1 NRTI

Etonogestrel

Androgen antagonist

Clindamycin phosphate

blocking bacterial protein synthesis

Ethinyl Estradiol Vaginal Ring

Androgen antagonist

Benzoyl Peroxide

Dermatologic agent

Estrogen

Androgen antagonist

Olmesartan Medoxomil

angiotensin II receptor antagonist

Progesterone

progesterone and estrogen receptors agonist

Hydrochlorothiazide

diuretic

Buprenorphine HCl

 opioid receptor partial agonist

Amlodipine Besylate

Ca2+ channel blocker

Naloxone Hcl

 opioid receptor antagonist

Atorvastatin Calcium

HMG-CoA reductase inhibitor

Budesonide

anti-inflammatory corticosteroid

Ciprofloxacin (0.3%)

topoisomerase II/IV inhibitor

Formoterol

2 adrenergic receptor agonist

Dexamethasone (0.1%)

anti-inflammatory corticosteroid

Calcipotriene

unknown

Ipratropium

mAChR antagonist

Betamethasone Dipropionate

anti-inflammatory corticosteroid

Salbutamol

-agonist

Tenofovir

HIV-1 NRTI

Lamivudine

HIV-1 NRTI

Emtricitabine

HIV-1 NRTI

Zidovudine

HIV-1 NRTI

Hydrocodone

unknown

Valsartan

angiotensin II receptor antagonist

Chlorpheniramine

H1 antagonist

Hydrochlorothiazide

diuretic

Ezetimibe

Cholesterol absorption inhibitor

Abacavir

HIV-1 NRTI

Simvastatin

HMG-CoA reductase inhibitor

Lamivudine

HIV-1 NRTI

Drospirenone

Progesterone receptor antagonist

Exforge

Amlodipine Besylate

Ca2+ channel blocker

Ethinyl Estradiol

Androgen antagonist



Valsartan

angiotensin II receptor antagonist

Omeprazole

H+/K + ATPase inhibitor

Hyzaar

Losartan Potassium

angiotensin II receptor antagonist

Sodium Bicarbonate

antacid

Hydrochlorothiazide

diuretic

Aggrenox

Atripla

BenzaClin

Benicar HCT

Caduet

Ciprodex Otic

Combivent

Combivir

Diovan HCT

Epzicom

Lotrel

Micardis HCT

NuvaRing

Ortho Tri-Cyclen Lo

Suboxone

Symbicort

Taclonex

Truvada

Tussionex

Vytorin

Yaz

Zegerid


1302 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

plementary pathways. In doing so, the optimal therapeutic outcome can be achieved. The exception to the complementary pathways appears to be the oral contraceptives and the anti-HIV drugs. Part of the reason for anti-HIV combinational drugs targeting the same enzyme may be attributed to that fact that HIV-1 mutations often desensitize routine clinical drugs. The addition of the structurally different inhibitors to the regimen would improve efficacy against HIV-1 mutants. For example, Atripla combines non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz with nucleotide analogue reverse transcriptase inhibitors (NRTI) emtricitabine and tenofovir. DRUG METABOLISM OF TOP 200 PHARMACEUTICALS Other than the molecular parameters that affect the oral absorption of drugs, aspects critical for the efficacy of a drug include distribution and metabolism. Understanding the drug metabolism is very critical as the risk of drug-drug interaction (DDI) increases when one drug inhibits the metabolism of another combined drug, resulting in an increased plasma drug concentration. It is estimated that approximately 26% of the two million serious adverse drug reactions were related to the avoidable DDIs [21]. Table 9 listed the metabolism of the low molecular weight drugs among the top 200 list. The metabolizing enzymes of each drug in Table 9 were extracted from SuperCyp database [9]. This table shows that some drugs were excreted from the body without any metabolism, whereas most common drugs are metabolized by one or more cytochrome P450 (CYP) proteins. Metabolism represented the most clearance mechanism for 73% of the top 200 most prescribed drugs in 2002. Among these metabolized drugs, approximately 73% were metabolized by cytochrome P450 proteins (CYP). Among the CYP proteinsmediated metabolisms, CYP3A accounted for 46%, followed by 16% for CYP2C9, 12% for CYP2C19 and CYP2D6 [22]. Cytochromes P450 (CYPs) are a family of a hemecontaining proteins that catalyze the metabolism of a variety of drug molecules. CYP3A family accounts for approximately 30% of hepatic P450, followed by 20% CYP2C9, and 13% CYP1A2. Other human CYP450 isozymes that are heavily involved in drug metabolism include 1A2, 2C9, and 2C19 [23]. Classification of drugs according to their metabolizing enzymes showed that CYP3A4 metabolized 103 drugs (out of 185 small molecules), i.e., 55.7% low MW drugs metabolized by CYP3A4, followed by CYP2D6 (63, 34.1%), CYP2C9 (59, 31.9%), CYP2C8 (43, 23.2%), CYP3A5 (26, 14.1%), CYP1A2 (25, 13.5%), CYP2B6 (12, 7.0%), and CYP2A6 (12, 6.5%) (Fig. 1). Although CYP2D6 is found in only 4% of human liver microsome, it metabolizes 34.1% of top 200 most prescribed drugs. This is in accordance with observations from other laboratories that CYP2D6 is involved in metabolizing approximately 30% of known drugs [24]. It is noted that isozymes 2C8 and 3A5 are among the top five CYP proteins that catalyze these top prescribed medicines. Previously, some observed 3A4, 2D6, 2C9, 2C19, and 1A2 as the isozymes metabolizing 90% of known drugs [25]. Our data confirm 3A4, 2D6 and 2C9 as the top three CYP proteins catalyzing drugs, but our metabolizing

Zhong et al.

enzyme data show that 1A2 metabolizes only 13.5% , and 2C19 only 5.98% of top prescribed drugs in 2010. This discrepancy might be attributed to the population size and chemical structures of different drugs between our studies and others, it might also be caused by the extent of accuracy of the metabolizing enzymes compiled in SuperCyp and other databases. The mean and standard deviation of molecular properties of drugs metabolized by CYP 3A4, 2D6, 2C9, and 2C8 are given in Table 10. On average, drugs metabolizing by 3A4 have larger molecular weight, whereas those metabolized by 2D6 have smaller MW. This observation is in agreement with Sun’s data that CYP3A4 tends to favor larger molecules (60% CYP3A4 active compounds have MW > 400) [23]. The hydrophobicity parameters, (logP) surprisingly, are very close for drugs metabolized by 3A4, 2D6 or 2C9. The logP of 2C8-metabolized drugs, however, tends to be much smaller (2.0), suggesting that drugs metabolized by 2C8 isozyme tend to be more polar and more hydrophilic. This agrees with the larger polar surface areas (TPSA, 85.7 Å2) observed in these molecules. It is observed that CYP3A4 prefers metabolizing large, neutral compounds [26], CYP2C9 favors neutral and acidic molecules [27], and CYP2D6 preferentially binds to basic compounds or compounds with lower molecular weights [15, 28, 29]. CONCLUDING REMARKS Using the top 200 most prescribed drugs to study the molecular properties and metabolizing characteristics certainly has its merit. These successful drugs delineate the desirable ranges for MW, logP, TPSA and ADMET scores for orally available drugs as well as for the pharmaceuticals that are given as injectable, ocular and other routes. Information on the range of MW, logP, and TPSA of different classes of drugs will provide helpful information to researchers in the drug discovery field. The analyses of ADMET scores of drugs violating one or more RO5 criteria will set an alarm for using RO5 as the only filter in early stage of discovery and it shows the merit of using the ADMET score as an additional guideline for drug research. The information on the salts and the combinational therapy will offer ideas for pharmaceutical scientists to generate certain formulations to achieve best efficacy. Certainly, there are many more molecular properties that can be calculated and investigated for these drugs. These properties include solubility logS, pKa, drug-drug interactions, metabolites, and pharmacokinetic parameters like t1/2, clearance, and volume of distribution (Vd) and so on. Our data show that there’s no definite relationship between molecular properties and Vd (data not shown). It is known that clearance and Vd are the most difficult to predict due to the complex factors involved [15, 30]. It is worthy to point out that some of the molecular properties might change if a larger dataset is used. We downloaded 1,500 FDA approved drugs from the FDA website. Our analysis showed that the molecular properties for CNS drugs in the top 200 prescribed medicines are in line with 179 approved CNS drugs. Although the mean molecular weights for drugs in anticancer, anti-HIV, antihypertensives, and antibiotics differed between these two dataset, the mean


Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

Table 9.

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

Metabolism of Top 200 Prescribed Drugs.

Drug Name

3A4

2D6

2C9

2C8

Drug Name

3A4

Abacavir sulfate

Linezolid

Acyclovir

Lisdexamfetamine dimesylate

Adapalene

Lopinavir

S/inh

Alendronate sodium

Loratadine

S/inh/ind

Alfuzosin HCl

S

Amlodipine

S/inh

inh

S

S

Losartan potassium

inh

inh

Lubiprostone

Amoxicillin

Meloxicam

Anastrozole

inh

Aripiprazole

S

inh

Aspirin Inh

Atorvastatin

S/inh

Azelastine

S/inh

S

S/inh

inh

Benazepril HCl Bicalutamide

S/inh

inh

inh

S/ind

S/ind

Buprenorphine

inh

inh

Bupropion HCl

S

S/inh

Metformin HCl

S/inh

S/inh

S/inh

S

S/inh

S/inh

inh

inh

Methylphenidate HCl

S/inh

Metoprolol succinate

S/inh S/inh/ind

Inh

S

inh

Morphine sulfate

S

Moxifloxacin HCl

S

Mycophenolate mofetil Naloxone HCl

Candesartan cilexetil

S/inh

Capecitabine

S

S

Cefdinir

inh S

S inh

Nifedipine

S/inh

Norethindrone acetate

S

S/inh

inh

S/inh

inh

S

inh

S

Olanzapine

inh

Olmesartan medoxomil

Cinacalcet HCl

Olopatadine HCl

S

Omeprazole

S/inh/ind

inh

S/inh

Ondansetron

S/ind

S/inh

S

inh

Clavulanate Clindamycin phosphate

S/inh

Oseltamivir phosphate

Clonidine Clopidogrel bisulfate

inh

Norgestimate

Cilastatin

Ciprofloxacin HCl

inh S

S

Niacin

inh S

inh

Montelukast sodium

S

Calcipotriene

Celecoxib

inh

Mometasone furoate

Brimonidine tartrate

Carvedilol phosphate

S/inh/ind

Mesalamine

Modafinil

Bimatoprost Bosentan

inh

Metaxalone inh

S/inh

2C8

Meropenem S

Atomoxetine HCl

2C9

S/inh

Memantine HCl

S/inh

2D6

Oxcarbazepine S

S/inh

inh

Oxycodone HCl

S

S

1303


1304 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

Zhong et al.

(Table 9) contdâ&#x20AC;Ś.

Drug Name

3A4

2D6

2C9

2C8

Drug Name

3A4

2D6

2C9

2C8

Darifenacin HBr

Oxymorphone HCl

Darunavir ethanoate

Paliperidone

inh

inh

Paroxetine

inh

S/inh

inh

inh

Pioglitazone HCl

S/ind

inh

S/inh

S/inh

Piperacillin

inh

S/inh

inh

S/inh

inh

Quetiapine fumarate

S

S/inh

Rabeprazole

S/inh

Raloxifene HCl

S/inh

Desloratadine Desvenlafaxine succinate

inh S

inh

S/inh

Pemetrexed

Dexmethylphenidate HCl Diclofenac

S/inh

S

S/inh

S/inh

Dipyridamole

Pramipexole di-HCl

Docetaxel

S/inh

Donepezil HCl

S

Dorzolamide

S

Doxazosin

S

Doxycycline HCl

S/inh

Pravastatin S

Pregabalin S

S

S

Drospirenone

Raltegravir potassium

Duloxetine HCl

S/inh/ind

Dutasteride

S

Efavirenz

S/inh

inh

Eletriptan HBr

S/ind

S

Ramipril

inh

S

Epinephrine

inh

inh

Repaglinide

S/inh

Risedronate sodium

Emtricitabine Enalapril

Ranitidine

inh

Esomeprazole magnesium

S

Estradiol

S

S

Estrone

S

S

inh

Risperidone

S/inh

S/inh/ind

Rivastigmine tartrate

inh

inh

S

inh

Ropinirole S

S/inh

Rosiglitazone maleate

inh

Rosuvastatin calcium

S/inh

Salmeterol xinafoate

S

Sertraline HCl

S/inh

Ezetimibe

Sevoflurane

S

Famotidine

Sildenafil citrate Simvastatin

inh

S

Rizatriptan benzoate

Erlotinib Escitalopram oxalate

S/inh

S

inh

S/inh

S/inh inh S/inh

S/inh

S/inh

S/inh

S

S/inh

S/inh

inh

Fenofibrate

S

Fentanyl citrate

S/inh

Fexofenadine HCl

S

Finasteride

S

Fluconazole

inh

Fluticasone furoate

S

Tadalafil

S

Fluticatsone propionate

S

Tamsulosin HCl

S

Sitagliptin phosphate inh

inh

inh

inh

S/inh

S/inh S

Sodium valproate

inh

Solifenacin succinate

S

Ind/Inh

Sumatriptan succinate

S

inh


Understanding the Molecular Properties and Metabolism of Top Prescribed Drugs

Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

1305

(Table 9) contdâ&#x20AC;Ś. Drug Name

3A4

2D6

2C9

2C8

Drug Name

Fluvastatin

S/inh

S/inh

S/inh

S/inh

Tazobactam

S

S

S

Telmisartan

Formoterol fumarate Gabapentin

S

S

S

Ibandronate sodium

Terbinafine HCl

S/ind

Testosterone

S/inh

inh

Thalidomide S/inh

S/inh

S/inh

S/inh

Imipenem S

Irbesartan

inh

Irinotecan

S/inh

Tiotropium bromide

S

S

Tolterodine tartrate

S

S

S/inh

S/inh

inh

S/inh

S/inh

Tramadol HCl

S

S

S

S

S

S

Travoprost Triamcinolone acetnonide

Lamotrigine

Valaciclovir HCl S/inh

S

Topiramate

Lamivudine

Latanoprost

inh

S/inh

S/inh

Lenalidomide

Valsartan Vardenafil HCl

S/inh S

Letrozole

S

Varenicline tartrate

Levalbuterol HCl

S/inh

Venlafaxine HCl

S/inh

Voriconazole

S/inh

S/inh

Zidovudine

S

S

inh

Ziprasidone HCl

S/inh

S

S

Zoledronic acid S

S/inh

Levetiracetam Levocetirizine diHCl Levofloxacin Levothyroxine sodium Lidocaine

2C8

inh

marate

Hydrocodone

mide

2C9

inh

Tenofivir disoproxil fu-

Glimepiride

Ipratropium bro-

2D6

Temozolomide

Gemcitabine

Imatinib mesylate

3A4

S/inh

S/inh

S

S

Zolpidem tartrate

S/inh/ind

S

S

S/inh

Note: S: substrate, inh: inhibitor; and ind: inducer.

logP and TPSA for drugs in these two dataset were very close. For instance, the mean logP and TPSA for anti-HIV drugs listed in the top 200 drugs were 1.1 and 116.5, whereas the corresponding numbers were 1.1 and 111.5 for anti-HIV drugs approved by the FDA (46 entries, Table 11 vs. Table 4). This is consistent with data in Table 5 that the ADMET scores and logP of oral drugs were consistent between oral drugs in the top 200 list and those extracted from a much larger sample size. It needs to point out that we do not include the monoclonal antibody (mAb) and peptide drugs in this study because the large sizes of these molecules. However, the research activity of mAb is strong. The mAb and

peptides accounted for 9 out of 23 New Molecular Entity (NME) and New Biologic License Application (BLA) approved by the FDA in 2010. The trend is clear. There will be even more mAb and peptide drugs on the market and an increasing number of research laboratories from both academics and biotech industry will shift their resources to the research on the new mAb and peptide drugs. The computational chemistry and molecular descriptors have been applied extensively to small molecular drug discovery. The success of applying computational techniques and molecular or structural parameters to guide the development of peptide drugs remains to be seen.


1306 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 11

Zhong et al.

Table 10. The Mean Values (Standard Deviations) of Top Prescribed Drugs Classified by Metabolizing Enzymes.

CYPs

MW (Dalton)

logP

TPSA (Å2)

3A4

377.2 (112.7)

3.09 (1.9)

72.8 (38.3)

2D6

344.8 (78.3)

3.00 (1.7)

61.2 (31.5)

2C9

357.7 (96.7)

3.05 (2.1)

73.7 (35.3)

2C8

353.9 (112.6)

1.95 (2.4)

85.7 (39.3)

Table 11. The Mean Values (With the Standard Deviations) of Molecular Properties of the FDA Approved Drugs Classified by Common Clinical Indications.

Classes

Anti-CNS

Anticancer

Anti-HIV

Antihypertensives

Antibiotics/antifungals

MW

295 (41)

371 (186)

365 (161)

350 (124)

460 (262)

2.8 (0.6)

1.7 (2.9)

1.1 (3.0)

2.7 (1.9)

0.6 (2.9)

TPSA (Å )

48.0 (8.1)

96.9 (57.8)

111.5 (42.1)

84.7 (32.4)

149.6 (114.8)

Num. of Drugs

179

98

46

77

172

logP 2

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Fig. (1). Percent of drugs metabolized by members of the cytochrome P450 (CYP) superfamily.

CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.

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ACKNOWLEDGEMENTS We would like to thank Research Corporation for financial support in software purchase. The financial support from the UNO FIRE program is also acknowledged. The authors are also indebted to the following medicinal chemistry students: Alexander Braun, Seth Cornish, Jacob Hettenbaugh, Gia Hoang, Kevin Kawa, Yohei Kohno, Ryan Mathiesen, Charlotte McGinn, Kevin McKenna, Amanda Riesberg, Stephanie Veys, Adrienne Ashley, Codie Bourn, Jessica Chevalier, John Houlton, Michael Paz, Jonathan Person, Rebecca Scott, Tyler Splichal, Mallory Stevens, and Adnan Waheed. These students have made partial contribution and inspired the completion of this project.

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Received: January 06, 2013

Revised: April 12, 2013

Accepted: April 22, 2013

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