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

  • J Med Chem. 2012 Feb 23;55(4):1751-7. doi: 10.1021/jm201524g.
Vince S C Yeh  1 ,  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
Affiliations
  • 1. Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, United States.
PMID: 22263872 DOI: 10.1021/jm201524g
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.

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