Abstract:
:The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed nonacidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these noncarboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Azevedo CM,Watterson KR,Wargent ET,Hansen SV,Hudson BD,Kępczyńska MA,Dunlop J,Shimpukade B,Christiansen E,Milligan G,Stocker CJ,Ulven Tdoi
10.1021/acs.jmedchem.6b00685subject
Has Abstractpub_date
2016-10-13 00:00:00pages
8868-8878issue
19eissn
0022-2623issn
1520-4804journal_volume
59pub_type
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