Structure activity relationship of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives as P2Y6 receptor antagonists. (1st June 2021)

• Record Type: Journal Article
• Authors: Jung, Young-Hwan; Jain, Shanu; Gopinatth, Varun; Phung, Ngan B.; Gao, Zhan-Guo; Jacobson, Kenneth A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 41(2021)
• Publication Date: 2021-06-01
• Subjects: P2Y receptor -- Antagonist -- Purinergic -- Calcium mobilization -- Structure activity relationship; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128008
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: P2Y6 receptor (P2Y6 R) is a target for inflammatory, neurodegenerative and metabolic diseases. 6-Ethynyl substitution enhanced affinity of known 3-nitro-2-(trifluoromethyl)-2 H -chromene P2Y6 R antagonist. Flexibility of substitution was indicated, even with sterically extended chains. Key compounds displayed surmountable antagonism of UDP-induced production of inositol phosphates. Abstract: Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2 H -chromene antagonist 3 of the Gq -coupled P2Y6 receptor (P2Y6 R) were synthesized using a Sonogashira reaction to replace a 6-iodo group. The analogues were tested in a functional assay consisting of inhibition of calcium mobilization in P2Y6 R-expressing astrocytoma cells elicited by native P2Y6 R agonist UDP. 6-Ethynyl and 6-cyano groups were installed, and the alkynes were extended through both alkyl and aryl spacers. The most potent antagonists, with IC50 of ~1 µM, were found to be trialkylsilyl-ethynyl 7 and 8 (3–5 fold greater affinity than reference 3 ), t -butyl prop-2-yn-1-ylcarbamate 14 and p -carboxyphenyl-ethynyl 16 derivatives, and 3 and 8 displayed surmountable antagonism of UDP-induced production of inositol phosphates. Other chain-extended terminal carboxylate derivatives were less potent than the corresponding methyl ester derivatives. Thus, the 6 position in this chromene series is suitable for derivatization with flexibility of substitution, even with sterically extended chains, without losing P2Y6 R affinity. However, a 3-carboxylic acid or 3-ester substitution did not serve as a nitro bioisostere, as the affinity was eliminated. These compounds provide additional ligand tools for the underexplored P2Y6 R, which is a target for inflammatory, neurodegenerative and metabolic diseases.