| Literature DB >> 28374589 |
William McCoull1, Andrew Bailey2, Peter Barton1, Alan M Birch2, Alastair J H Brown2, Hayley S Butler2, Scott Boyd1, Roger J Butlin2, Ben Chappell2, Paul Clarkson1, Shelley Collins2, Robert M D Davies2, Anne Ertan2, Clare D Hammond2, Jane L Holmes2, Carol Lenaghan2, Anita Midha2, Pablo Morentin-Gutierrez1, Jane E Moore2, Piotr Raubo1, Graeme Robb1.
Abstract
GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.Entities:
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Year: 2017 PMID： 28374589 DOI： 10.1021/acs.jmedchem.7b00210
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446