Issue 1, 2013

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353

Abstract

Inhibition of diacylglycerol acetyl transferase 1 is of great interest in the treatment of diabetes, obesity and other diseases that constitute the metabolic syndrome. Small molecule inhibitors of the enzyme are often dogged with physicochemical property-related problems such as poor solubility. Herein, the optimisation of a series of biphenyl acetic acid inhibitors is reported. Focus on ligand efficiency and ligand lipophilicity efficiency and a strategy based on conformational restriction led to compounds with excellent potency and ADMET properties, culminating in the discovery of AZD2353.

Graphical abstract: Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353

Supplementary files

Article information

Article type
Concise Article
Submitted
11 Jul 2012
Accepted
26 Sep 2012
First published
25 Oct 2012

Med. Chem. Commun., 2013,4, 159-164

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353

M. J. Waring, A. M. Birch, S. Birtles, L. K. Buckett, R. J. Butlin, L. Campbell, P. M. Gutierrez, P. D. Kemmitt, A. G. Leach, P. A. MacFaul, C. O'Donnell and A. V. Turnbull, Med. Chem. Commun., 2013, 4, 159 DOI: 10.1039/C2MD20190A

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