Chimeras Derived from a P2Y₁₄ Receptor Antagonist and UDP-Sugar Agonists for Potential Treatment of Inflammation

Tethered glycoconjugates of a naphthalene- and piperidine-containing antagonist of the P2Y₁₄ receptor (PPTN) were synthesized, and their nM receptor binding affinity was determined using a fluorescent tracer in hP2Y₁₄R-expressing whole CHO cells. The rationale for preparing mono- and disaccharide conjugates of the antagonists was to explore the receptor binding site, which we know recognizes a glucose moiety on the native agonist (UDP-glucose), as well as enhance aqueous solubility and pharmacokinetics, including kidney excretion to potentially counteract sterile inflammation. Glycoconjugates with varied linker length, including PEG chains, were compared in hP2Y₁₄R binding, suggesting that an optimal affinity (IC₅₀, nM) in the piperidine series was achieved for triazolyl <i>N</i>-linked glucose conjugates having one (<b>8a</b>, MRS4872, 3.21) or two (<b>7a</b>, MRS4865, 2.40) methylene spacers. In comparison of different carbohydrate conjugates lacking a piperidine moiety but containing triazole spacers, optimal hP2Y₁₄R affinity (IC₅₀, nM) was achieved with <i>N</i>-linked glycosides of fucose <b>10f</b> (6.19) and lactose <b>10h</b> (1.88), and <i>C</i>-linked glucose <b>11a</b> (5.30). Selected compounds were examined in mouse models of conditions known to be ameliorated by P2Y₁₄R antagonists. Two glycoconjugates that lacked a piperidine moiety, <i>N</i>-linked glucose derivative <b>10a</b> and the isomeric <i>C</i>-linked glucose derivative <b>11a</b>, were protective in a mouse model of allergic asthma. Piperidine-containing glucose conjugate <b>7a</b> of intermediate linker length and corresponding glucuronide <b>7b</b> (MRS4866) protected against neuropathic pain. Thus, glycoconjugation of a known antagonist scaffold has produced less hydrophobic P2Y₁₄R antagonists having substantial in vitro and in vivo activity.