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Short Paper | Special issue | Vol 95, No. 1, 2017, pp.595-607
Published online, 15th December, 2016
DOI: 10.3987/COM-16-S(S)30
Structural Development Studies of Pyrazoloketone-Derived Acetyl-CoA Carboxylase Inhibitors

Shogo Okazaki, Taki Sakai, Minoru Ishikawa, Yuichi Hashimoto, and Takao Yamaguchi*

*Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Abstract

Acetyl-CoA carboxylase (ACC) plays a key role in fatty acid homeostasis in humans, and inhibitors of ACC are expected to inhibit fatty acid biosynthesis and to activate fatty acid β-oxidation. Therefore, they are considered to be candidates for treatment of metabolic syndrome and related diseases. In this context, an upstream kinase of ACC, adenosine monophosphate-activated protein kinase (AMPK), has also recently emerged as a potential therapeutic target, because it phosphorylates and inactivates ACC. Here, we designed a fused molecule consisting of a pyrazoloketone-type ACC inhibitor and a recently discovered AMPK activator, aiming to develop a novel combined ACC inhibitor/AMPK activator to regulate fatty acid levels. The designed compound was prepared through a convergent synthetic route. This compound and its methyl ester analogue showed potent ACC2-inhibitory activity with IC50 values of 8.8 and 1.3 μM, respectively. Exomethylene derivatives, obtained from an unexpected side reaction during deprotection, also exhibited ACC2-inhibitory activity.