Non-acidic free fatty acid receptor 4 agonists with antidiabetic activity

Azevedo, C. M. G. et al. (2016) Non-acidic free fatty acid receptor 4 agonists with antidiabetic activity. Journal of Medicinal Chemistry, 59(19), pp. 8868-8878. (doi:10.1021/acs.jmedchem.6b00685)

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 non-acidic 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 non-carboxylic 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Watterson, Dr Kenneth and Milligan, Professor Graeme and Hudson, Dr Brian and Dunlop, Mrs Julia
• Authors: Azevedo, C. M. G., Watterson, K. R., Wargent, E. T., Hansen, S. V. F., Hudson, B. D., Kępczyńska, M. A., Dunlop, J., Shimpukade, B., Christiansen, E., Milligan, G., Stocker, C. J., and Ulven, T.
• College/School: College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology; College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: Journal of Medicinal Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-2623
• ISSN (Online): 1520-4804
• Published Online: 29 August 2016
• Copyright Holders: Copyright © 2016 American Chemical Society
• First Published: First published in Journal of Medicinal Chemistry 59(19):8868-8878
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher