Structure activity relationship of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives as P2Y 6 receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 41; p. 128008
• Main Authors: Jung, Young-Hwan, Jain, Shanu, Gopinatth, Varun, Phung, Ngan B, Gao, Zhan-Guo, Jacobson, Kenneth A
• Format: Journal Article
• Language: English
• Published: England 01.06.2021
• Subjects: Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; Dose-Response Relationship, Drug; Humans; Molecular Structure; Purinergic P2Y Receptor Antagonists - chemical synthesis; Purinergic P2Y Receptor Antagonists - chemistry; Purinergic P2Y Receptor Antagonists - pharmacology; Receptors, Purinergic P2 - metabolism; Structure-Activity Relationship; Calcium mobilization; Structure activity relationship; P2Y receptor; Purinergic; Antagonist
• ISSN: 1464-3405

Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2H-chromene antagonist 3 of the G -coupled P2Y receptor (P2Y 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 P2Y R-expressing astrocytoma cells elicited by native P2Y 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 IC 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 P2Y 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 P2Y R, which is a target for inflammatory, neurodegenerative and metabolic diseases.