Design and Discovery of a Selective Small Molecule 魏 Opioid Antagonist (2-Methyl-N-((2鈥?(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242)

详细信息    查看全文

• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5868-5877
• 全文大小：1022K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

By use of parallel chemistry coupled with physicochemical property design, a series of selective 魏 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 魏 antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure鈥搑esponse relationship between the 魏 K_i and the free brain drug levels. This strategy identified 2-methyl-N-((2鈥?(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.