Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA: diacylglycerol acyltransferase 1

…, J Gao, N Grihalde, P Hajduk, TM Hansen…

Index: Yeh, Vince S. C.; Beno, David W. A.; Brodjian, Sevan; Brune, Michael E.; Cullen, Steven C.; Dayton, Brian D.; Dhaon, Madhup K.; Falls, Hugh D.; Gao, Ju; Grihalde, Nelson; Hajduk, Philip; Hansen, T. Matthew; Judd, Andrew S.; King, Andrew J.; Klix, Russel C.; Larson, Kelly J.; Lau, Yau Y.; Marsh, Kennan C.; Mittelstadt, Scott W.; Plata, Dan; Rozema, Michael J.; Segreti, Jason A.; Stoner, Eric J.; Voorbach, Martin J.; Wang, Xiaojun; Xin, Xili; Zhao, Gang; Collins, Christine A.; Cox, Bryan F.; Reilly, Regina M.; Kym, Philip R.; Souers, Andrew J. Journal of Medicinal Chemistry, 2012 , vol. 55, # 4 p. 1751 - 1757

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Citation Number: 26

Abstract

A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses≥ 0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to ...