Achieving improved permeability by hydrogen bond donor modulation in a series of MGAT2 inhibitors

James S. Scott; David J. Berry; Hayley S. Brown; Linda Buckett; David S. Clarke; Kristin Goldberg; Julian A. Hudson; Andrew G. Leach; Philip A. MacFaul; Piotr Raubo; Graeme Robb

doi:10.1039/C3MD00156C

Achieving improved permeability by hydrogen bond donor modulation in a series of MGAT2 inhibitors†

James S. Scott,*^a David J. Berry,^b Hayley S. Brown,^a Linda Buckett,^a David S. Clarke,^a Kristin Goldberg,^a Julian A. Hudson,^a Andrew G. Leach,^a Philip A. MacFaul,^a Piotr Raubo^a and Graeme Robb^a

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^a AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK
E-mail: jamie.scott@astrazeneca.com
Fax: +44 (0)1625 516667
Tel: +44 (0)1625 232567

^b Durham University, School of Medicine, Pharmacy and Health, Wolfson Research Institute, Queen's Campus, Stockton on Tees, UK

Abstract

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.

MedChemComm

Achieving improved permeability by hydrogen bond donor modulation in a series of MGAT2 inhibitors†

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Achieving improved permeability by hydrogen bond donor modulation in a series of MGAT2 inhibitors

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