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

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 <b>14</b>. 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 <b>14</b> as clinical candidate ABT-046