11 But it was the Topliss Tree that resonated most prominently with medicinal chemists. Hundreds of researchers have cited the Topliss Tree methodology in their publications, and application of the Topliss Tree during the early stages of SAR optimization has facilitated development of several commercially successful drugs. The Topliss Tree has also served medicinal chemists by redirecting their efforts away from inactive chemical analogs and allowing them to rapidly abandon unproductive compound synthesis campaigns.
Forty years ago, when he was sitting alone at his desk quietly sketching out his ideas, Topliss “did not in my wildest dreams expect this to be the outcome.”
References 1. H ansch C and Fujita T (1964) ρ – σ – π Analysis. A method for the correlation of biological activity and chemical structure. J Am Chen Soc 86(8): 1616-1626.
The Topliss Tree methodology is only one of many tools used in designing a viable drug. But despite the advent of more sophisticated methods such as molecular modeling based on X-ray crystallography data and the willingness of today’s synthetic chemists to readily embrace computational chemistry, the Topliss Tree remains a valuable and frequently used tool in the medicinal chemist’s toolbox. Forty years ago, when he was sitting alone at his desk quietly sketching out his ideas, Topliss “did not in my wildest dreams expect this to be the outcome.” For their outstanding contributions to medicinal chemistry, Corwin Hansch and John Topliss have both received many honors. Hansch received the American Chemical Society’s Smissman Award in 1976, and Topliss received the ACS Division of Medicinal Chemistry Award in 1998. Both were inducted into the ACS Division of Medicinal Chemistry Hall of Fame in 2007. 5. H ansch C (1974) A computerized approach to quantitative biochemical structure-activity relationships, in Biological Correlations—The Hansch Approach (Van Valkenberg W ed) pp 20-40, American Chemical Society, Washington, DC.
2. S elassie C and Verma RP (2010) History of quantitative structure-activity relationships, in Burger’s Medicinal Chemistry, Drug Discovery and Development (Abraham DJ and Rotella DP eds) 7th ed, vol. 1, pp 1-77, Wiley, New York.
6. T opliss JG (1972) Utilization of operational schemes for analog synthesis in drug design. J Med Chem 15(10): 1006-1011.
3. H ansch C (2011) The advent and evolution of QSAR at Pomona College. J Comput Aided Mol Des 25: 495-507.
8. D eWitt SH, Kiely JS, Stankovic CJ, Schroeder MC, Cody DMR, and Pavi MR (1993) “Diversomers”: An approach to nonpeptide, nonoligomeric chemical diversity. Proc Natl Acad Sci U S A 90:6909-6913.
4. M augh TH (2011) Corwin Hansch dies at 92: Scientist whose advances led to new drugs and chemicals. Los Angeles Times, May 23.
7. T opliss JG (1977) A manual method for applying the Hansch approach to drug design. J Med Chem 20(4): 463-469.
9. Y oshida F and Topliss JG (2000) QSAR model for drug human oral bioavailability. J Med Chem 43:2575-2585, 2000.
Reprinted from The Pharmacologist • March 2014