Piperazine Oxadiazole Inhibitors of Acetyl-CoA Carboxylase

被引：17

作者：

Bourbeau, Matthew P. ^{[1
]}

Siegmund, Aaron ^{[1
]}

Allen, John G. ^{[1
]}

Shu, Hong ^{[1
]}

Fotsch, Christopher ^{[1
]}

Bartberger, Michael D. ^{[1
]}

Kim, Ki-Won ^{[2
]}

Komorowski, Renee ^{[2
]}

Graham, Melissa ^{[2
]}

Busby, James ^{[2
,3
]}

Wang, Minghan ^{[2
,3
]}

Meyer, James ^{[3
]}

Xu, Yang

Salyers, Kevin

Fielden, Mark ^{[4
]}

Veniant, Murielle M. ^{[2
]}

Gu, Wei ^{[2
]}

机构：

[1] Amgen Inc, Therapeut Discovery, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Metab Dis Res, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Pharmacokinet Drug Metab, Thousand Oaks, CA 91320 USA

[4] Amgen Inc, Comparat Biol & Safety Sci, Thousand Oaks, CA 91320 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 24期

关键词：

FATTY-ACID OXIDATION; ENERGY-EXPENDITURE; METABOLIC-SYNDROME; MUTANT MICE; DESIGN; KNOCKOUT; MASS;

D O I：

10.1021/jm401601s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Acetyl-CoA carboxylase (ACC) is a target of interest for the treatment of metabolic syndrome. Starting from a biphenyloxadiazole screening hit, a series of piperazine oxadiazole ACC inhibitors was developed. Initial pharmacokinetic liabilities of the piperazine oxadiazoles were overcome by blocking predicted sites of metabolism, resulting in compounds with suitable properties for further in vivo studies. Compound 26 was shown to inhibit malonyl-CoA production in an in vivo pharmacodynamic assay and was advanced to a long-term efficacy study. Prolonged dosing with compound 26 resulted in impaired glucose tolerance in diet-induced obese (DIO) CS7BL6 mice, an unexpected finding.

引用

页码：10132 / 10141

页数：10

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