Q1 · MEDICINE
Article
Author: Lau, Yau Y. ; Wang, Xiaojun ; Hajduk, Philip ; Xin, Xili ; Plata, Dan ; Reilly, Regina M. ; Dayton, Brian D. ; Collins, Christine A. ; Grihalde, Nelson ; Judd, Andrew S. ; Brune, Michael E. ; Yeh, Vince S. C. ; Cullen, Steven C. ; Zhao, Gang ; Brodjian, Sevan ; Marsh, Kennan C. ; Dhaon, Madhup K. ; Rozema, Michael J. ; Kym, Philip R. ; Falls, Hugh D. ; King, Andrew J. ; Mittelstadt, Scott W. ; Voorbach, Martin J. ; Gao, Ju ; Cox, Bryan F. ; Hansen, T. Matthew ; Klix, Russel C. ; Larson, Kelly J. ; Segreti, Jason A. ; Stoner, Eric J. ; Beno, David W. A. ; Souers, Andrew J.
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.