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

Citations Over TimeTop 17% of 2013 papers

Abstract

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.

Related Papers

• → De novo fatty acid synthesis in developing rat lung(1982)57 cited
• → Acetyl-CoA Carboxylase of Sheep Adipose Tissue: Problems of the Assay and Adaptation During Fetal Development(1986)10 cited
• → Biotin Carboxyl Carrier Protein and Biotin Carboxylase Subunits of the Multi Subunit form of Acetyl CoA Carboxylase from Brassica Napus(1997)1 cited
• → Regulation of fatty acid synthesis in lactating rat mammary gland in the fed to starved transition: Asynchronous control of pyruvate dehydrogenase, phosphofructokinase and acetyl-CoA carboxylase(1991)3 cited
• → Effect of Knockout of Two Acetyl-CoA Carboxylase Isoforms in the Isolated Mouse Heart on Oxidation of Exogenous and Endogenous Energy Sources(2023)