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)

被引：42

作者：

Verhoest, Patrick R. ^{[1
]}

Basak, Aarti Sawant ^{[1
]}

Parikh, Vinod ^{[1
]}

Hayward, Matthew ^{[1
]}

Kauffman, Gregory W. ^{[1
]}

Paradis, Vanessa ^{[1
]}

McHardy, F. ^{[1
]}

McLean, Stafford ^{[1
]}

Grimwood, Sarah ^{[1
]}

Schmidt, Anne W. ^{[1
]}

Vanase-Frawley, Michelle ^{[1
]}

Freeman, Jodi ^{[1
]}

Van Deusen, Jeffrey ^{[1
]}

Cox, Loretta ^{[1
]}

Wong, Diane ^{[1
]}

Liras, Spiros ^{[1
]}

机构：

[1] Pfizer PharmaTherapeut Res & Dev, Neurosci Med Chem, Groton, CT USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 16期

关键词：

CENTRAL-NERVOUS-SYSTEM; RECEPTOR ANTAGONIST; IN-VITRO; P-GLYCOPROTEIN; POTENT; IDENTIFICATION; ALIGNMENT; BUPRENORPHINE; METABOLISM; BINDING;

D O I：

10.1021/jm2006035

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

By use of parallel chemistry coupled with physicochemical property design, a series of selective kappa 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 kappa antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure-response relationship between the kappa 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.

引用

页码：5868 / 5877

页数：10

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