Identification and Preliminary Characterization of a Potent, Safe, and Orally Efficacious Inhibitor of Acyl-CoA:Diacylglycerol Acyltransferase 1

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• 作者：Vince S. C. Yeh ; David W. A. Beno ; Sevan Brodjian ; Michael E. Brune ; Steven C. Cullen ; Brian D. Dayton ; Madhup K. Dhaon ; Hugh D. Falls ; Ju Gao ; Nelson Grihalde ; Philip Hajduk ; T. Matthew Hansen ; Andrew S. Judd ; Andrew J. King ; Russel C. Klix ; Kelly J. Larson ; Yau Y. Lau ; Kennan C. Marsh ; Scott W. Mittelstadt ; Dan Plata ; Michael J. Rozema ; Jason A. Segreti ; Eric J. Stoner ; Martin J. Voorbach ; Xiaojun Wang ; Xili Xin ; Gang Zhao ; Christine A. Collins ; Bryan F. Cox ; Regina M. Reilly ; Philip R. Kym ; Andrew J. Souers
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 23, 2012
• 年：2012
• 卷：55
• 期：4
• 页码：1751-1757
• 全文大小：290K
• 年卷期：v.55,no.4(February 23, 2012)
• ISSN：1520-4804

文摘

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 鈮?.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 high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.