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)

Patrick R Verhoest; Aarti Sawant Basak; Vinod Parikh; Matthew 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 Cox; Diane Wong; Spiros Liras

doi:10.1021/jm2006035

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)

J Med Chem. 2011 Aug 25;54(16):5868-77. doi: 10.1021/jm2006035. Epub 2011 Jul 22.

Authors

Patrick R Verhoest¹, Aarti Sawant Basak, Vinod Parikh, Matthew 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 Cox, Diane Wong, Spiros Liras

Affiliation

¹ Neuroscience Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA. patrick.r.verhoest@pfizer.com

PMID: 21744827
DOI: 10.1021/jm2006035

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.

MeSH terms

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
Analgesics / chemistry
Analgesics / pharmacokinetics
Analgesics / pharmacology
Animals
Area Under Curve
Biphenyl Compounds / chemistry
Biphenyl Compounds / pharmacokinetics
Biphenyl Compounds / pharmacology*
Brain / metabolism
Disease Models, Animal
Dogs
Drug Design*
Drug Discovery*
Haplorhini
Humans
Metabolic Clearance Rate
Mice
Microsomes, Liver / metabolism
Models, Chemical
Molecular Structure
Morphine / pharmacology
Narcotic Antagonists / chemistry
Narcotic Antagonists / pharmacokinetics
Narcotic Antagonists / pharmacology*
Pain / metabolism
Pain / prevention & control
Rats
Rats, Sprague-Dawley
Receptors, Opioid, kappa / agonists
Receptors, Opioid, kappa / antagonists & inhibitors*
Receptors, Opioid, kappa / metabolism
Receptors, Opioid, mu / agonists
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology*

Substances

2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine
Analgesics
Biphenyl Compounds
Narcotic Antagonists
Receptors, Opioid, kappa
Receptors, Opioid, mu
Sulfonamides
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
Morphine