Discovery and Characterization of an Inhibitor of Glucosylceramide Synthase
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- 作者：Steven Richards ; Christopher J. Larson ; Elena S. Koltun ; Art Hanel ; Vicky Chan ; Jason Nachtigall ; Amanda Harrison ; Naing Aay ; Hongwang Du ; Arlyn Arcalas ; Adam Galan ; Jeff Zhang ; Wentao Zhang ; Kwang-Ai Won ; Danny Tam ; Fawn Qian ; Tao Wang ; Patricia Finn ; Kathy Ogilvie ; Jon Rosen ; Ron Aoyama ; Artur Plonowski ; Belinda Cancilla ; Frauke Bentzien ; Michael Yakes ; Raju Mohan ; Peter Lamb ; John Nuss ; Patrick Kearney
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：May 10, 2012
- 年：2012
- 卷：55
- 期：9
- 页码：4322-4335
- 全文大小：748K
- 年卷期：v.55,no.9(May 10, 2012)
- ISSN：1520-4804
文摘
Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC50 of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.