The Importance of Molecular Design Principles in Delivering High Quality Pharmaceutical Candidates
High throughput screening of large chemical libraries of compounds is a proven way to identify novel chemical entities that target a biological system of interest. This technology is being used by industry and a growing number of academic screening centers for drug discovery campaigns. Unfortunately, many of the components of screening libraries have poor drug-like properties and require optimization. Typical components of a screening hit that need to be optimized include water solubility, reduced potential for toxicity, and metabolic stability. Presently, methods to alter individual molecular properties are not well elucidated. This chapter will discuss the molecular design principles that have been used successfully to alter the physiochemical properties of molecules through medicinal chemistry. Insights will be provided into the differences in approaches needed for optimization of a biological probe for target validation versus that of a hit to lead campaign, the design of more drug-like libraries, and the over-reliance of potency in optimization campaigns.
KeywordsChemical Probe Furan Ring Biological Target Kappa Opioid Receptor Trifluoromethyl Group
This chapter is based in part on a short course in Contemporary Medicinal Chemistry given by Professors Lester A. Mitscher and Thomas E. Prisinzano provided by the International Organization for Chemical Sciences in Development (IOCD). The author wishes to thank the National Institute on Drug Abuse (DA018151) for financial support of the medicinal chemistry described in the case study. The content is the sole responsibility of the author and does not necessarily represent the official views of the National Institute on Drug Abuse, National Institutes of Health.
- Beguin C, Potter DN, Dinieri JA, Munro TA, Richards MR, Paine TA, Berry L, Zhao Z, Roth BL, Xu W, Liu-Chen LY, Carlezon WA Jr, Cohen BM (2008) N-methylacetamide analog of salvinorin A: a highly potent and selective kappa-opioid receptor agonist with oral efficacy. J Pharmacol Exp Ther 324(1):188–195PubMedCrossRefGoogle Scholar
- Simonson B, Morani AS, Ewald AW, Walker L, Kumar N, Simpson D, Miller JH, Prisinzano TE, Kivell BM (2014) Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A. Br J Pharmacol doi: 10.1111/bph.12692Google Scholar
- Simpson DS, Katavic PL, Lozama A, Harding WW, Parrish D, Deschamps JR, Dersch CM, Partilla JS, Rothman RB, Navarro H, Prisinzano TE (2007) Synthetic studies of neoclerodane diterpenes from Salvia divinorum: preparation and opioid receptor activity of salvinicin analogues. J Med Chem 50(15):3596–3603PubMedCrossRefGoogle Scholar