Design and synthesis of a novel series of cyclohexyloxy-pyridyl derivatives as inhibitors of diacylglycerol acyl transferase 1

Alleyn T. Plowright, Peter Barton, Stuart Bennett, Alan M. Birch, Susan Birtles, Linda K. Buckett, Roger J. Butlin, Robert D. M. Davies, Anne Ertan, Pablo Morentin Gutierrez, Paul D. Kemmitt, Andrew G. Leach, Per H. Svensson, Andrew V. Turnbull, Michael J. Waring

Research output: Contribution to journalArticlepeer-review

Abstract

A novel series of potent diacylglycerol acyl transferase 1 inhibitors was developed from the clinical candidate AZD3988. Replacement of the phenyl cyclohexyl-ethanoate side chain with substituted oxy-linked side chains to introduce changes in shape and polarity, reduce lipophilicity and mask the hydrogen bond donors with internal hydrogen bond acceptors led to improvements in solubility, unbound clearance and excellent selectivity over the related enzyme acyl-coenzyme A:cholesterol acyltransferase 1. A comparison of the small molecule crystal structures of compound 4 and compound 28 is described. Compounds in this series have good ADMET properties and provide an exposure-dependent decrease in circulating plasma triglyceride levels in a rat oral lipid tolerance test.

Original languageEnglish
Pages (from-to)151-158
Number of pages7
JournalMedChemComm
Volume4
Issue number1
DOIs
Publication statusPublished - Jan 2013

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