Issue 1, 2013

Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors

Abstract

A series of neutral DGAT1 inhibitors with good potency and pharmacokinetics (PK) has been designed by modification of an acidic startpoint. This was achieved by selecting the acid with the highest ligand lipophilicity efficiency (LLE) and replacing the acid with neutral isosteres. PK properties (Fabs) were then improved by removing the sidechain to reduce molecular weight and polar surface area (PSA). Compound 13 has shown good cross-species PK, with pre-clinical efficacy and PK/PD relationships comparable to those previously described for acidic inhibitors.

Graphical abstract: Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors

Supplementary files

Article information

Article type
Concise Article
Submitted
06 Aug 2012
Accepted
13 Sep 2012
First published
01 Oct 2012

Med. Chem. Commun., 2013,4, 165-174

Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors

F. W. Goldberg, A. M. Birch, A. G. Leach, S. D. Groombridge, W. L. Snelson, P. M. Gutierrez, C. D. Hammond, S. Birtles and L. K. Buckett, Med. Chem. Commun., 2013, 4, 165 DOI: 10.1039/C2MD20231J

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