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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.

Original publication




Journal article


J Med Chem

Publication Date





5258 - 5269


Animals, Azepines, Blood-Brain Barrier, CHO Cells, Central Nervous System Agents, Cricetulus, Dogs, Drug Design, Humans, Madin Darby Canine Kidney Cells, Permeability, Pyrimidines, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2B, Receptor, Serotonin, 5-HT2C, Serotonin 5-HT2 Receptor Agonists, Structure-Activity Relationship, Urinary Incontinence, Stress