P2Y₁₄ Receptor Antagonists: Piperidine Bioisosteres and Mutagenesis-Supported Molecular Modeling.

ABSTRACT: The human P2Y₁₄ receptor (hP2Y₁₄R) has emerged as a promising target for inflammation and pain treatment, but its zwitterionic antagonists have low bioavailability. We extended the naphthalene-based antagonist series' structure-activity relationship (SAR) by replacing an outward-facing piperidine moiety with small heteroaromatics. Notably, C-linked 1,2,3-triazol-4-yl (10, MRS4916) and pyrazol-3-yl (11, MRS4917) substitutions yielded antagonists with IC₅₀ values of 3.69 and 2.88 nM, respectively. In contrast, incorporation of a second triazole in the phenyl-triazolyl series (16) significantly reduced affinity. Charged phosphate groups were strategically placed at two positions of potent triazole derivative 7 to explore the

SUBMITTER: Pramanik A 

PROVIDER: S-EPMC12441858 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature