Design and discovery of a selective small molecule κ opioid antagonist (2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242).
作者： Patrick R. Verhoest , Aarti Sawant Basak , Vinod Parikh , Matthew Hayward , Gregory W. Kauffman
DOI: 10.1021/JM2006035
关键词:
摘要: By use of parallel chemistry coupled with physicochemical property design, a series selective κ opioid antagonists have been discovered. The strategy utilized key monomer building blocks to rapidly expand the desired SAR space. potency and selectivity in vitro antagonism were confirmed tail-flick analgesia model. This model was used build an exposure–response relationship between Ki free brain drug levels. identified 2-methyl-N-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing has demonstrated target engagement healthy volunteers.
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