Bioorganic & Medicinal Chemistry Letters 2011-10-01

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

Hashim Motiwala, 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

Index: Bioorg. Med. Chem. Lett. 21(19) , 5812-7, (2011)

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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.Copyright © 2011 Elsevier Ltd. All rights reserved.