Spirolactam-Based Acetyl-CoA Carboxylase Inhibitors: Toward Improved Metabolic Stability of a Chromanone Lead Structure

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• 作者：David A. Griffith ; Robert L. Dow ; Kim Huard ; David J. Edmonds ; Scott W. Bagley ; Jana Polivkova ; Dongxiang Zeng ; Carmen N. Garcia-Irizarry ; James A. Southers ; William Esler ; Paul Amor ; Kathrine Loomis ; Kirk McPherson ; Kevin B. Bahnck ; Cathy Pr茅ville ; Tereece Banks ; Dianna E. Moore ; Alan M. Mathiowetz ; Elnaz Menhaji-Klotz ; Aaron C. Smith ; Shawn D. Doran ; David A. Beebe ; Matthew F. Dunn
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：7110-7119
• 全文大小：433K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide 21, which was advanced to preclinical development.