| Literature DB >> 30247908 |
Anders Højgaard Hansen1, Eugenia Sergeev2, Daniele Bolognini2, Richard R Sprenger3, Jeppe Hvidtfeldt Ekberg4, Christer S Ejsing3, Christine J McKenzie1, Elisabeth Rexen Ulven1,5, Graeme Milligan2, Trond Ulven1,5.
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 clog P) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.Entities:
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Year: 2018 PMID： 30247908 DOI： 10.1021/acs.jmedchem.8b00855
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446