Hansen, A. H., Sergeev, E. , Bolognini, D., Sprenger, R. R., Ekberg, J. H., Ejsing, C. S., McKenzie, C. J., Rexen Ulven, E., Milligan, G. and Ulven, T. (2018) Discovery of a potent thiazolidine free fatty acid receptor 2 agonist with favorable pharmacokinetic properties. Journal of Medicinal Chemistry, 61(21), pp. 9534-9550. (doi: 10.1021/acs.jmedchem.8b00855) (PMID:30247908)
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Abstract
Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation and inflammatory responses, and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal and hepatocyte stability, favorable pharmacokinetic properties, and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Bolognini, Dr Daniele and Sergeev, Miss Eugenia and Milligan, Professor Graeme |
| Authors: | Hansen, A. H., Sergeev, E., Bolognini, D., Sprenger, R. R., Ekberg, J. H., Ejsing, C. S., McKenzie, C. J., Rexen Ulven, E., Milligan, G., and Ulven, T. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences 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: | 24 September 2018 |
| Copyright Holders: | Copyright © 2018 American Chemical Society |
| First Published: | First published in Journal of Medicinal Chemistry 61(21): 9534-9550 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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