Discovery of a potent thiazolidine free fatty acid receptor 2 agonist with favorable pharmacokinetic properties

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 > 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: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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
659371Designer Receptor Exclusively Activated by Designer Drug' to define the role of short chain fatty acids in metabolic disease and inflammation (Fatty acid DREADD)Graeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/L027887/1RI MOLECULAR CELL & SYSTEMS BIOLOGY