Publication of the week: Buckingham Institute for Translational Medicine

7 November 2016

Carlos M. G. Azevedo, Kenneth R. Watterson, Ed T. Wargent, Steffen V. F. Hansen, Brian D. Hudson, Małgorzata A. Kępczyńska, Julia Dunlop, Bharat Shimpukade, Elisabeth Christiansen, Graeme Milligan, Claire J. Stocker & Trond Ulven, “Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity”, Journal of Medicinal Chemistry 59 (19), 8868–8878. DOI: 10.1021/acs.jmedchem.6b00685.

The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, the authors report preliminary structure–activity relationship studies of a previously disclosed nonacidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these noncarboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4.

Read more on the Journal of Medicinal Chemistry website and the Buckingham E-Archive of Research (BEAR).

Ed T. Wargent, Małgorzata A. Kępczyńska and Claire J. Stocker are Research Fellows in the Buckingham Institute for Translational Medicine. The other authors are from the Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, and the Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow.

Claire Stocker was awarded her BSc (Hons) Biochemistry from the University of Southampton (1992) and a PhD from Imperial College, London (1999). She was awarded the IASO New Investigator Award in 2002 shortly after joining the School of Science and Medicine. Claire originally worked in the Clore Lab from 1999-2002. She returned in 2003 after spending a year at GlaxoSmithKline. Her current interests are the identification of the underlying molecular mechanisms in the regulation of energy balance both centrally and in adipose tissue. Claire has more than 50 peer-reviewed publications to her name. Claire is also Student Support Lead and Phase 1 Module Lead for Metabolism in the undergraduate Medical School.

Małgorzata Kępczyńska was awarded an MA in Biology (2006) at the University of Szczecin in Poland. In 2006 Małgorzata joined the Clore Lab where she obtained an MSc in Biomedical Science (2009) and was also awarded a DPhil in Biomedical Science (2014). Since 2014 Małgorzata has been working as a Research Fellow in the Lab. She is co-ordinator of the Nuffield Secondary School placement scheme in the Lab and a Personal Tutor in the Medical School at The University of Buckingham. She has 23 peer-reviewed publications to her name.

Ed Wargent was awarded a BSc in Biochemistry in 1993 from the University of Glasgow and an MSc in Toxicology in 1994 from the University of Surrey. Since 1999 Ed has worked in the Clore Laboratory, where his interests include treatment of obesity and type 2 diabetes and related disorders, insulin resistance and insulin secretion and regulation of energy expenditure and food intake, amongst others. Ed has around 30 peer-reviewed publications to his name.