DOI: https://doi.org/10.24959/ophcj.20.210383

The synthesis of cis- and trans-3-(4-hydroxyphenyl)cyclobutanecarboxylic acids and the study of their derivatives as GPR-40 receptor ligands

I. O. Feskov, I. S. Kondratov, Yu. O. Kuchkovska, V. S. Naumchyk, O. V. Onopchenko, O. O. Grygorenko

Abstract


Aim. To synthesize cis- and trans-isomers of 3-(4-hydroxyphenyl)cyclobutanecarboxylic acid and evaluate the biological activity of their derivatives against GPR-40.

Results and discussion. Cis- and trans-isomers of 3-(4-hydroxyphenyl)cyclobutanecarboxylic acid were synthesized. The derivatives of this compound were tested as GPR-40 agonists and exhibited the micromolar activity.

Experimental part. The methyl ester of 3-(4-hydroxyphenyl)cyclobutanecarboxylic acid was obtained as a mixture of cis/trans-isomers in 3 steps starting from a commercially available 3-oxocyclobutanecarboxylic acid. Further transformation of this compound into isomerically pure 3-(4-hydroxyphenyl)cyclobutanecarboxylic acids was achieved in five steps based on the chromatographic separation of diastereomeric amide derivatives. New GPR-40 ligands were obtained by O-alkylation of a phenolic oxygen atom of the corresponding carboxylic acid methyl ester. The biological activity of the agonists synthesized was studied using a fluorometric bioassay and the engineered Chinese hamster ovary (CHO) stable cell line expressing the human GPR-40.

Conclusions. An effective synthetic approach to 3-(4-hydroxyphenyl)cyclobutanecarboxylic acid allowing to isolate two single cis/trans-stereoisomers of this compound has been developed. In order to demonstrate the possibility for the bioisosteric replacement of the ethylene moiety in the structures of free fatty acid receptor (FFAR) agonists by the cyclobutane ring, four new GPR-40 ligands possessing the micromolar activity have been synthesized.

Received: 22.08.2020
Revised: 11.10.2020
Accepted: 17.10.2020


Keywords


cyclobutane; GPR-40; FFAR; agonist; diabetes mellitus

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Abbreviated key title: J. Org. Pharm. Chem.

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