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.
MeSH terms
-
Animals
-
Azepines / chemical synthesis
-
Azepines / chemistry*
-
Azepines / pharmacology
-
Blood-Brain Barrier / metabolism
-
CHO Cells
-
Central Nervous System Agents / chemical synthesis
-
Central Nervous System Agents / chemistry*
-
Central Nervous System Agents / pharmacology
-
Cricetulus
-
Dogs
-
Drug Design
-
Humans
-
Madin Darby Canine Kidney Cells
-
Permeability
-
Pyrimidines / chemical synthesis
-
Pyrimidines / chemistry*
-
Pyrimidines / pharmacology
-
Receptor, Serotonin, 5-HT2A / metabolism*
-
Receptor, Serotonin, 5-HT2B / metabolism*
-
Receptor, Serotonin, 5-HT2C / metabolism*
-
Serotonin 5-HT2 Receptor Agonists / chemical synthesis
-
Serotonin 5-HT2 Receptor Agonists / chemistry*
-
Serotonin 5-HT2 Receptor Agonists / pharmacology
-
Structure-Activity Relationship
-
Urinary Incontinence, Stress / drug therapy
Substances
-
2-(difluoro(phenyl)methyl)-N-methyl-6,7,8,9-tetrahydro-5H-pyrimido(4,5-d)azepin-4-amine
-
2-benzyl-9-methyl-4-(methylamino)-5,6,8,9-tetrahydro-7H-pyrimido(4,5-d)azepine
-
Azepines
-
Central Nervous System Agents
-
Pyrimidines
-
Receptor, Serotonin, 5-HT2A
-
Receptor, Serotonin, 5-HT2B
-
Receptor, Serotonin, 5-HT2C
-
Serotonin 5-HT2 Receptor Agonists