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)
Journal of Medicinal Chemistry2011Vol. 54(16), pp. 5868–5877
Citations Over TimeTop 12% of 2011 papers
Patrick R. Verhoest, Aarti Sawant Basak, Vinod D. Parikh, Matthew M. Hayward, Gregory W. Kauffman, Vanessa Paradis, Stanton F. McHardy, Stafford McLean, Sarah Grimwood, Anne W. Schmidt, Michelle Vanase‐Frawley, Jodi Freeman, Jeffrey Van Deusen, Loretta M. Cox, Diane Wong, Spiros Liras
Abstract
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 κ K(i) 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.
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