文摘
By use of parallel chemistry coupled with physicochemical property design, a series of selective 魏 opioid antagonists have been discovered. The parallel chemistry strategy utilized key monomer building blocks to rapidly expand the desired SAR space. The potency and selectivity of the in vitro 魏 antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure鈥搑esponse relationship between the 魏 Ki and the free brain drug levels. This strategy identified 2-methyl-N-((2鈥?(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers.