1. Academic Validation
  2. Exploration of pyridine containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors

Exploration of pyridine containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors

  • Bioorg Med Chem Lett. 2011 Oct 1;21(19):5812-7. doi: 10.1016/j.bmcl.2011.07.109.
Hashim Motiwala 1 Shivaji Kandre Vishal Birar Kishorkumar S Kadam Atish Rodge Ravindra D Jadhav M Mahesh Kumar Reddy Manoja K Brahma Nitin J Deshmukh Amol Dixit Lalit Doshi Amol Gupte Ashok K Gangopadhyay Ram A Vishwakarma Shaila Srinivasan Mamta Sharma Kumar V S Nemmani Rajiv Sharma
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Piramal Life Sciences Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India.
Abstract

The diacylglycerol Acyltransferase enzyme, DGAT1, presents itself as a potential target for obesity as this Enzyme is dedicated to the final committed step in triglyceride biosynthesis. Biphenyl ureas, exemplified by compound 4, have been reported to be potent hDGAT1 inhibitors. We have synthesized and evaluated 2-pyridyl and 3-pyridyl containing biaryl ureas as hDGAT1 inhibitors. Our aim was to incorporate a heteroaryl scaffold within these molecules thereby improving the cLogP profile and making these compounds more drug-like. Compounds within this series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Selected compounds were also subjected to an oral fat tolerance test in mice where the percent triglyceride reduction versus a vehicle control was evaluated. Of the studied heteroaryl analogs compound 44 exhibited an in vitro IC(50) of 17nM and a plasma triglyceride reduction of 79% along with a 12-fold improvement in solubility over the biphenyl urea compound 4.

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