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

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journal contribution
posted on 22.02.2016, 05:01 by 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
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 high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.