Document Report Card

ID: ALA2163253

Journal: J Med Chem

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

Authors: Yeh VS, Beno DW, Brodjian S, Brune ME, Cullen SC, Dayton BD, Dhaon MK, Falls HD, Gao J, Grihalde N, Hajduk P, Hansen TM, Judd AS, King AJ, Klix RC, Larson KJ, Lau YY, Marsh KC, Mittelstadt SW, Plata D, Rozema MJ, Segreti JA, Stoner EJ, Voorbach MJ, Wang X, Xin X, Zhao G, Collins CA, Cox BF, Reilly RM, Kym PR, Souers AJ.

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

CiteXplore: 22263872

DOI: 10.1021/jm201524g