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

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

Affiliation

  • 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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