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DavidsonX – D001x – Medicinal Chemistry Chapter 10 – Lead Discovery Part 6 – Selective Optimization of Side Activities Video Clip – SOSA Not all hits are found through random screening. One alternative to HTS of a molecular library is called selective optimization of side activities or SOSA.1 The idea of taking a molecule with a primary activity in humans and then enhancing a secondary effect through structural changes describes the most common implementation of SOSA. An advantage to starting a drug discovery program with molecules that have already been tested in humans is that those molecules have already satisfied many safety criteria. With so many drugs failing because of toxic effects, it is natural for a premium to be placed upon safety at the lead discovery stage. Molecules that have been tested in humans also likely have favorable pharmacokinetic profiles. The primary approach for SOSA involves creating a molecular library populated with compounds that have been tested in humans and possibly approved as drugs. The included molecules should affect a broad range of protein targets. The drug library is then used as a starting point and screened against new protein targets. Any hits will presumably have a high potential for clearing the typical hurdles (membrane permeability, metabolism inhibition, etc.) that keep hits from becoming leads.1 A different SOSA approach, which is less deliberate and more opportunistic, takes a molecule with a known side effect and attempts to enhance the side effect activity. Perhaps the most famous example of this SOSA approach is sildenafil. O O O





sildenafil (Viagra) erectile dysfunction




Sildenafil was a drug in development for the treatment of angina, a condition in which heart muscle does not receive enough oxygen. In early phase trials, sildenafil was found to be poorly effective in the treatment of angina. When the trial was canceled, patients were slow to return their unused medication. It was soon discovered that sildenafil held promise as a treatment of erectile dysfunction. Sildenafil, the angina clinical candidate, become sildenafil, a lead for the treatment of erectile dysfunction. Sildenafil was later approved and became one of the most financially successful drugs in the history of pharmaceuticals. 2 Sildenafil is an atypical example of a SOSA drug. Sildenafil was ineffective in its original use and yet was effective and approved without a single molecular change for a completely different use. It is generally assumed that a SOSA program will require structural modifications to optimize the desired effect of the lead. 1. Wermuth, C. Selective Optimization of Side Activities: Another Way for Drug Discovery. J. Med. Chem. 2004, 47, 1303-1314. 2. Kling, J. From Hypertension to Angina to Viagra. Mod. Drug. Disc. 1998, 1, 31-38.

MOOC Medicinal Chemistry