Multiparameter Optimization in CNS Drug Discovery: Design of Pyrimido[4,5-d]azepines as Potent 5-Hydroxytryptamine 2C (5-HT2C) Receptor Agonists with Exquisite Functional Selectivity
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- 作者：R. Ian Storer ; Paul E. Brennan ; Alan D. Brown ; Peter J. Bungay ; Kelly M. Conlon ; Matthew S. Corbett ; Robert P. DePianta ; Paul V. Fish ; Alexander Heifetz ; Danny K. H. Ho ; Alan S. Jessiman ; Gordon McMurray ; Cesar Augusto F. de Oliveira ; Lee R. Roberts ; James A. Root ; Veerabahu Shanmugasundaram ; Michael J. Shapiro ; Melanie Skerten ; Dominique Westbrook ; Simon Wheeler ; Gavin A. Whitlock ; John Wright
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：June 26, 2014
- 年：2014
- 卷：57
- 期：12
- 页码：5258-5269
- 全文大小：608K
- ISSN：1520-4804
文摘
A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.