Discovery and characterization of an inhibitor of glucosylceramide synthase

…, A Hanel, V Chan, J Nachtigall, A Harrison…

Index: Richards, Steven; Larson, Christopher J.; Koltun, Elena S.; Hanel, Art; Chan, Vicky; Nachtigall, Jason; Harrison, Amanda; Aay, Naing; Du, Hongwang; Arcalas, Arlyn; Galan, Adam; Zhang, Jeff; Zhang, Wentao; Won, Kwang-Ai; Tam, Danny; Qian, Fawn; Wang, Tao; Finn, Patricia; Ogilvie, Kathy; Rosen, Jon; Aoyama, Ron; Plonowski, Artur; Cancilla, Belinda; Bentzien, Frauke; Yakes, Michael; Mohan, Raju; Lamb, Peter; Nuss, John; Kearney, Patrick Journal of Medicinal Chemistry, 2012 , vol. 55, # 9 p. 4322 - 4335

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Citation Number: 8

Abstract

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 ...