Synthesis and biological evaluation of isoxazole, oxazole, and oxadiazole containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors.

Abstract

Diacylglycerol acyltransferase, DGAT1, is a promising target enzyme for obesity due to its involvement in the committed step of triglyceride biosynthesis. Amino biphenyl carboxylic acids, exemplified by compound 4, are known potent inhibitors of hDGAT1. However the high cLogP and poor solubility of these biphenyl analogs might tend to limit their development. We have synthesized and evaluated compounds containing 3-phenylisoxazole, 5-phenyloxazole, and 3-phenyl-1,2,4-oxadiazole biaryl units for their hDGAT1 inhibition. Our aim in synthesizing such heterocyclic analogs was to improve the cLogP and solubility of these molecules while retaining hDGAT1 potency. Several compounds within the 3-phenylisoxazole series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Certain promising compounds were studied for their potential to reduce triglyceride levels using an in vivo fat tolerance test in mice and were also evaluated for any possible improvement to their solubility. Compound 40a (IC(50) = 64 nM) with an in vivo plasma triglyceride reduction of 90 percent, and a solubility of 0.43 mg/ml at pH 7.4 may serve as a new lead for developing newer anti-obesity agents.

• Authors: Ravindra D Jadhav, Kishorkumar S Kadam, Shivaji Kandre, Tandra Guha, M Mahesh Kumar Reddy, Manoja K Brahma, Nitin J Deshmukh, Amol Dixit, Lalit Doshi, Nisha Potdar, Arno A Enose, Ram A Vishwakarma, H Sivaramakrishnan, Shaila Srinivasan, Kumar V S Nemmani, Amol Gupte, Ashok K Gangopadhyay, Rajiv Sharma
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 54 Pg. 324-42 (Aug 2012) ISSN: 1768-3254 [Electronic] France
• PMID: 22683241 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Isoxazoles
• Oxadiazoles
• Water
• Urea
• Diacylglycerol O-Acyltransferase

Topics

• Animals
• Chemistry Techniques, Synthetic
• Diacylglycerol O-Acyltransferase (antagonists & inhibitors)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Inhibitory Concentration 50
• Isoxazoles (chemical synthesis, chemistry, pharmacology)
• Mice
• Oxadiazoles (chemical synthesis, chemistry, pharmacology)
• Solubility
• Structure-Activity Relationship
• Urea (chemistry)
• Water (chemistry)