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 over 5-HT₂A and 5-HT₂B receptors

  • J Med Chem. 2014 Jun 26;57(12):5258-69. doi: 10.1021/jm5003292.
R Ian Storer  1 ,  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
Affiliations
  • 1. Discovery Chemistry, ‡Discovery Biology, and §Pharmacokinetics, Dynamics and Metabolism, Sandwich Laboratories, Pfizer Global Research and Development , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
PMID: 24878222 DOI: 10.1021/jm5003292
Abstract

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.

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