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.
Subject(s)
Azepines/chemistry , Central Nervous System Agents/chemistry , Pyrimidines/chemistry , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/chemistry , Animals , Azepines/chemical synthesis , Azepines/pharmacology , Blood-Brain Barrier/metabolism , CHO Cells , Central Nervous System Agents/chemical synthesis , Central Nervous System Agents/pharmacology , Cricetulus , Dogs , Drug Design , Humans , Madin Darby Canine Kidney Cells , Permeability , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/pharmacology , Structure-Activity Relationship , Urinary Incontinence, Stress/drug therapyABSTRACT
A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT(2C) agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT(2C) agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT(2B). Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.
Subject(s)
Azepines/chemistry , Pyrimidines/chemistry , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/chemistry , Urinary Incontinence/drug therapy , Animals , Azepines/chemical synthesis , Azepines/pharmacology , CHO Cells , Cell Line , Cricetinae , Cricetulus , Dogs , Drug Discovery , Humans , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Recombinant Proteins/agonists , Recombinant Proteins/metabolism , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/pharmacology , TransfectionABSTRACT
The title reagent engaged in the modified Julia olefination with aldehydes under mild reaction conditions (DBU, CH(2)Cl(2), rt or -78 degrees C) to yield alpha,beta-unsaturated esters; aryl aldehydes and aliphatic aldehydes possessing significant chain branching elements gave trans alkene products with high stereoselectivity (E : Z up to >98 : 2), while straight chain aliphatic aldehydes gave cis products preferentially (Z : E up to 92 : 8).
