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) Full article

Journal

Bioorganic Chemistry
ISSN: 0045-2068 , E-ISSN: 1090-2120

Output data

Year: 2020, Volume: 99, Article number : 103830, Pages count : DOI: 10.1016/j.bioorg.2020.103830

Tags

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

Authors

Kuranov Sergey O. ¹ , Luzina Olga A. ¹ , Onopchenko Oleksandra ² , Pishel Iryna ² , Zozulya Sergey ^2,3 , Gureev Maxim ⁴ , Salakhutdinov Nariman F. ¹ , Krasavin Mikhail ⁵

Affiliations

1	(Данные Web of science) Russian Acad Sci, NN Vorozhtsov Novosibirsk Inst Organ Chem, Siberian Branch, Novosibirsk 630090, Russia
2	(Данные Web of science) Enamine Ltd, UA-02094 Kiev, Ukraine
3	(Данные Web of science) IM Taras Shevchenko Natl Univ, 62 Volodymyrska, UA-01033 Kiev, Ukraine
4	(Данные Web of science) IM Sechenov First Moscow State Med Univ, Moscow 119991, Russia
5	(Данные Web of science) St Petersburg State Univ, St Petersburg 199034, Russia

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.

Kuranov S.O. , Luzina O.A. , Onopchenko O. , Pishel I. , Zozulya S. , Gureev M. , Salakhutdinov N.F. , Krasavin M.
Exploring bulky natural and natural -like periphery in the design of p-(benzyloxy)phenylpropionic acid agonists of free fatty acid receptor 1 (GPR40)
Bioorganic Chemistry. 2020. V.99. 103830 . DOI: 10.1016/j.bioorg.2020.103830 WOS Scopus РИНЦ

Published print:

Jun 1, 2020

Web of science	WOS:000535444000005
Scopus	2-s2.0-85083018442
Elibrary	43267125
OpenAlex	W3016093134