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Issue 1, 2013
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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

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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

  • This article is part of the themed collection: New Talent
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Publication details

The article was received on 06 Aug 2012, accepted on 13 Sep 2012 and first published on 01 Oct 2012


Article type: Concise Article
DOI: 10.1039/C2MD20231J
Citation: Med. Chem. Commun., 2013,4, 165-174
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    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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