Achieving improved permeability by hydrogen bond donor modulation in a series of MGAT2 inhibitorsElectronic supplementary information (ESI) available. See DOI: 10.1039/c3md00156c

Monoacylglycerolacetyltransferase-2 (MGAT2) is a potential target for the treatment of type II diabetes. We report here the optimisation of a series of MGAT2 inhibitors with regard to their potency and permeability. Improvements in permeability, as measured by increased flux in a Caco-2 assay, were...

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Main Authors: Scott, James S, Berry, David J, Brown, Hayley S, Buckett, Linda, Clarke, David S, Goldberg, Kristin, Hudson, Julian A, Leach, Andrew G, MacFaul, Philip A, Raubo, Piotr, Robb, Graeme
Format: Article
Language:English
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Summary:Monoacylglycerolacetyltransferase-2 (MGAT2) is a potential target for the treatment of type II diabetes. We report here the optimisation of a series of MGAT2 inhibitors with regard to their potency and permeability. Improvements in permeability, as measured by increased flux in a Caco-2 assay, were achieved through substitution at the 9-position of the core. We propose that reduction of the NH hydrogen-bond donor strength was primarily responsible for these effects. Permeability improvements are achieved through modulation of hydrogen bond donor strength rather than increasing lipophilicity.
ISSN:2040-2503
2040-2511
DOI:10.1039/c3md00156c