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

Frederick W. Goldberg, Alan M. Birch, Andrew G. Leach, Sam D. Groombridge, Wendy L. Snelson, Pablo Morentin Gutierrez, Clare D. Hammond, Susan Birtles, Linda K. Buckett

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)165-174
JournalMedChemComm
Volume4
Issue number1
DOIs
Publication statusPublished - Jan 2013

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