1322001-02-4Relevant articles and documents
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)
Verhoest, Patrick R.,Sawant Basak, Aarti,Parikh, Vinod,Hayward, Matthew,Kauffman, Gregory W.,Paradis, Vanessa,McHardy, Stanton F.,McLean, Stafford,Grimwood, Sarah,Schmidt, Anne W.,Vanase-Frawley, Michelle,Freeman, Jodi,Van Deusen, Jeffrey,Cox, Loretta,Wong, Diane,Liras, Spiros
, p. 5868 - 5877 (2011/10/08)
By use of parallel chemistry coupled with physicochemical property design, a series of selective κ 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 κ antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure-response relationship between the ? Ki and the free brain drug levels. This strategy identified 2-methyl-N-((2′- (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.
