2. Academic Validation
  3. Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties

Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties

  • J Med Chem. 2018 Nov 8;61(21):9534-9550. doi: 10.1021/acs.jmedchem.8b00855.
Anders Højgaard Hansen 1,  Eugenia Sergeev 2,  Daniele Bolognini 2,  Richard R Sprenger 3,  Jeppe Hvidtfeldt Ekberg 4,  Christer S Ejsing 3,  Christine J McKenzie 1,  Elisabeth Rexen Ulven 1 5,  Graeme Milligan 2,  Trond Ulven 1 5
Affiliations

Affiliations

  • 1 Department of Physics, Chemistry and Pharmacy , University of Southern Denmark , Campusvej 55 , DK-5230 Odense M, Denmark.
  • 2 Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences , University of Glasgow , Glasgow G12 8QQ , Scotland, United Kingdom.
  • 3 Department of Biochemistry and Molecular Biology , University of Southern Denmark , Campusvej 55 , DK-5230 Odense M, Denmark.
  • 4 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences , University of Copenhagen , Blegdamsvej 3 , 2200 Copenhagen , Denmark.
  • 5 Department of Drug Design and Pharmacology , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark.
PMID: 30247908 DOI: 10.1021/acs.jmedchem.8b00855
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.

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