Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

  • J Med Chem. 2017 Jun 8;60(11):4657-4664. doi: 10.1021/acs.jmedchem.7b00173.
Katsumasa Nakajima  1 ,  Ricardo Chatelain  1 ,  Kevin B Clairmont  1 ,  Renee Commerford  1 ,  Gary M Coppola  1 ,  Thomas Daniels  1 ,  Cornelia J Forster  1 ,  Thomas A Gilmore  1 ,  Yongjin Gong  1 ,  Monish Jain  1 ,  Aaron Kanter  1 ,  Youngshin Kwak  1 ,  Jingzhou Li  1 ,  Charles D Meyers  1 ,  Alan D Neubert  1 ,  Paul Szklennik  1 ,  Vivienne Tedesco  1 ,  James Thompson  1 ,  David Truong  1 ,  Qing Yang  1 ,  Brian K Hubbard  1 ,  Michael H Serrano-Wu  1
Affiliations
  • 1. Global Discovery Chemistry, ‡Cardiovascular and Metabolism, ∥PK Sciences, and §Translational Medicine, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
PMID: 28498655 DOI: 10.1021/acs.jmedchem.7b00173
Abstract

Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.

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