Indazole-6-phenyl­cyclopropyl­carboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy

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)-c...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 60; no. 7; pp. 3187 - 3197
Main Authors: McCoull, William, Bailey, Andrew, Barton, Peter, Birch, Alan M, Brown, Alastair J. H, Butler, Hayley S, Boyd, Scott, Butlin, Roger J, Chappell, Ben, Clarkson, Paul, Collins, Shelley, Davies, Robert M. D, Ertan, Anne, Hammond, Clare D, Holmes, Jane L, Lenaghan, Carol, Midha, Anita, Morentin-Gutierrez, Pablo, Moore, Jane E, Raubo, Piotr, Robb, Graeme
Format: Journal Article
Language:English
Published: American Chemical Society 13-04-2017
Online Access:Get full text
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b00210