Discovery of potent tetrazole free fatty acid receptor 2 antagonists

Valentini, A., Schultz-Knudsen, K., Højgaard Hansen, A., Tsakoumagkou, A., Jenkins, L. , Christensen, H. B., Manandhar, A., Milligan, G. , Ulven, T. and Rexen Ulven, E. (2023) Discovery of potent tetrazole free fatty acid receptor 2 antagonists. Journal of Medicinal Chemistry, 66(9), pp. 6105-6121. (doi: 10.1021/acs.jmedchem.2c01935) (PMID:37129317)

Abstract

The free fatty acid receptor 2 (FFA2), also known as GPR43, mediates effects of short-chain fatty acids and has attracted interest as a potential target for treatment of various metabolic and inflammatory diseases. Herein, we report the results from bioisosteric replacement of the carboxylic acid group of the established FFA2 antagonist CATPB and SAR investigations around these compounds, leading to the discovery of the first high-potency FFA2 antagonists, with the preferred compound TUG-2304 (16l) featuring IC50 values of 3–4 nM in both cAMP and GTPγS assays, favorable physicochemical and pharmacokinetic properties, and the ability to completely inhibit propionate-induced neutrophil migration and respiratory burst.

• Item Type: Articles
• Additional Information: This work was supported by the Lundbeck Foundation (grant #R181-2014-3247 and #R307-2018-2950, both to E.R.U.), the Novo Nordisk Foundation (grant #NNF21OC0069019, to T.U.), the Innovation Fund Denmark (grant #0603-00452B, to T.U.), and the Biotechnology and Biological Sciences Research Council, U.K. (grant #BB/X001814/1, to G.M.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Milligan, Professor Graeme and Jenkins, Mrs Laura
• Authors: Valentini, A., Schultz-Knudsen, K., Højgaard Hansen, A., Tsakoumagkou, A., Jenkins, L., Christensen, H. B., Manandhar, A., Milligan, G., Ulven, T., and Rexen Ulven, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Journal of Medicinal Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-2623
• ISSN (Online): 1520-4804
• Published Online: 02 May 2023
• Copyright Holders: Copyright © 2023 American Chemical Society
• First Published: First published in Journal of Medicinal Chemistry 66(9): 6105-6121
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
317075		novel roles of the short chain fatty acid receptors FFA2 and FFA3	Graeme Milligan	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/X001814/1	School of Molecular Biosciences