title: 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).
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.
authors: Neuroscience Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA. patrick.r.verhoest@pfizer.com
authors: Patrick R
authors: PR
authors: Verhoest
authors: Aarti Sawant
authors: AS
authors: Basak
authors: Vinod
authors: V
authors: Parikh
authors: Matthew
authors: M
authors: Hayward
authors: Gregory W
authors: GW
authors: Kauffman
authors: Vanessa
authors: V
authors: Paradis
authors: Stanton F
authors: SF
authors: McHardy
authors: Stafford
authors: S
authors: McLean
authors: Sarah
authors: S
authors: Grimwood
authors: Anne W
authors: AW
authors: Schmidt
authors: Michelle
authors: M
authors: Vanase-Frawley
authors: Jodi
authors: J
authors: Freeman
authors: Jeffrey
authors: J
authors: Van Deusen
authors: Loretta
authors: L
authors: Cox
authors: Diane
authors: D
authors: Wong
authors: Spiros
authors: S
authors: Liras
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000700:Analgesics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001713:Biphenyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D015195:Drug Design; D055808:Drug Discovery; D000882:Haplorhini; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010146:Pain / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C568463:2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine; D000700:Analgesics; D001713:Biphenyl Compounds; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013449:Sulfonamides; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine