PF-3774076

PF-3774076 is a highly central nervous system (CNS) penetrant, potent, and selective human α1A-adrenoceptor partial agonist. It exhibits good potency and selectivity in multiple binding and functional assays. PF-3774076 increases peak urethral pressure in anesthetized female dogs in a dose-dependent manner via a central mechanism. PF-3774076 affects both the proximal and distal portions of the urethra in vivo. These properties suggest that PF-3774076 may have significant benefit in the treatment of stress urinary incontinence (SUI) as a CNS-penetrant α1A receptor partial agonist. However, despite its partial agonism and selectivity for α1A receptors, PF-3774076 failed to provide adequate safety differences in in vivo models of cardiovascular function. This may be due to the simultaneous activation of both peripheral and central α1A receptors. These data suggest that while central α1A partial agonists may have significant benefit in the treatment of SUI, this class of agents may have difficulty achieving the desired urethral selectivity without affecting cardiovascular function.