Piperazine Oxadiazole Inhibitors of Acetyl-CoA Carboxylase
详细信息 查看全文
- 作者：Matthew P. Bourbeau ; Aaron Siegmund ; John G. Allen ; Hong Shu ; Christopher Fotsch ; Michael D. Bartberger ; Ki-Won Kim ; Renee Komorowski ; Melissa Graham ; James Busby ; Minghan Wang ; James Meyer ; Yang Xu ; Kevin Salyers ; Mark Fielden ; Murielle M. Véniant ; Wei Gu
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：December 27, 2013
- 年：2013
- 卷：56
- 期：24
- 页码：10132-10141
- 全文大小：614K
- ISSN：1520-4804
文摘
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) C57BL6 mice, an unexpected finding.