2. Academic Validation
  3. Exploring bulky natural and natural-like periphery in the design of p-(benzyloxy)phenylpropionic acid agonists of free fatty acid receptor 1 (GPR40)

Exploring bulky natural and natural-like periphery in the design of p-(benzyloxy)phenylpropionic acid agonists of free fatty acid receptor 1 (GPR40)

  • Bioorg Chem. 2020 Jun;99:103830. doi: 10.1016/j.bioorg.2020.103830.
Sergey O Kuranov 1,  Olga A Luzina 1,  Oleksandra Onopchenko 2,  Iryna Pishel 2,  Sergey Zozulya 3,  Maxim Gureev 4,  Nariman F Salakhutdinov 1,  Mikhail Krasavin 5
Affiliations

Affiliations

  • 1 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russian Federation.
  • 2 Enamine Ltd, Kyiv 02094, Ukraine.
  • 3 Enamine Ltd, Kyiv 02094, Ukraine; Taras Shevchenko National University, 62 Volodymyrska, Kyiv 01033, Ukraine.
  • 4 I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russian Federation.
  • 5 Saint Petersburg State University, Saint Petersburg 199034, Russian Federation. Electronic address: m.krasavin@spbu.ru.
PMID: 32289588 DOI: 10.1016/j.bioorg.2020.103830
Abstract

Six derivatives of 3-phenylpropionic acid bearing various natural and natural-like, spatially defined peripheral motifs have been synthesized and evaluated in vitro for Free Fatty Acid Receptor 1 (FFA1) activation. Two frontrunner compounds (bearing a bornyl and cytosine groups) were evaluated in an oral glucose tolerance test in mice where both demonstrated the ability to sustain blood glucose levels following a glucose challenge. The bornyl compound displayed a somewhat superior, dose-dependent efficacy and, therefore, can be regarded as a lead compounds for further development as a therapeutic agent for type 2 diabetes mellitus. Its high affinity to FFA1 was rationalized by docking experiments.

Keywords

Free fatty acid receptor 1; Glucose tolerance; Natural products; Natural-likeness; Three-dimensional structure; Type 2 diabetes mellitus.

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