Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

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• 作者：Bruce A. Ellsworth ; Philip M. Sher ; Ximao Wu ; Gang Wu ; Richard B. Sulsky ; Zhengxiang Gu ; Natesan Murugesan ; Yeheng Zhu ; Guixue Yu ; Doree F. Sitkoff ; Kenneth E. Carlson ; Liya Kang ; Yifan Yang ; Ning Lee ; Rose A. Baska ; William J. Keim ; Mary Jane Cullen ; Anthony V. Azzara ; Eva Zuvich ; Michael A. Thomas ; Kenneth W. Rohrbach ; James J. Devenny ; Helen E. Godonis ; Susan J. Harvey ; Brian J. Murphy ; Gerry G. Everlof ; Paul I. Stetsko ; Olafur Gudmundsson ; Susan Johnghar ; Asoka Ranasinghe ; Kamelia Behnia ; Mary Ann Pelleymounter ; William R. Ewing
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9586-9600
• 全文大小：581K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.