Chimeras Derived from a P2Y<sub>14</sub> Receptor\nAntagonist and UDP-Sugar Agonists for Potential Treatment of Inflammation

Tethered\nglycoconjugates of a naphthalene- and piperidine-containing\nantagonist of the P2Y<sub>14</sub> receptor (PPTN) were synthesized,\nand their nM receptor binding affinity was determined using a fluorescent\ntracer in hP2Y<sub>14</sub>R-expressing whole CHO cells. The rationale\nfor preparing mono- and disaccharide conjugates of the antagonists\nwas to explore the receptor binding site, which we know recognizes\na glucose moiety on the native agonist (UDP-glucose), as well as enhance\naqueous solubility and pharmacokinetics, including kidney excretion\nto potentially counteract sterile inflammation. Glycoconjugates with\nvaried linker length, including PEG chains, were compared in hP2Y<sub>14</sub>R binding, suggesting that an optimal affinity (IC<sub>50</sub>, nM) in the piperidine series was achieved for triazolyl <i>N</i>-linked glucose conjugates having one (<b>8a</b>,\nMRS4872, 3.21) or two (<b>7a</b>, MRS4865, 2.40) methylene spacers.\nIn comparison of different carbohydrate conjugates lacking a piperidine\nmoiety but containing triazole spacers, optimal hP2Y<sub>14</sub>R\naffinity (IC<sub>50</sub>, 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\nknown to be ameliorated by P2Y<sub>14</sub>R antagonists. Two glycoconjugates\nthat lacked a piperidine moiety, <i>N</i>-linked glucose\nderivative <b>10a</b> and the isomeric <i>C</i>-linked\nglucose derivative <b>11a</b>, were protective in a mouse model\nof 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\nof a known antagonist scaffold has produced less hydrophobic P2Y<sub>14</sub>R antagonists having substantial in vitro and in vivo activity.