Papers of the Week

Tethered glycoconjugates of a naphthalene- and piperidine-containing antagonist of the P2Y receptor (PPTN) were synthesized, and their nM receptor binding affinity was determined using a fluorescent tracer in hP2YR-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 hP2YR binding, suggesting that an optimal affinity (IC, nM) in the piperidine series was achieved for triazolyl -linked glucose conjugates having one (, MRS4872, 3.21) or two (, MRS4865, 2.40) methylene spacers. In comparison of different carbohydrate conjugates lacking a piperidine moiety but containing triazole spacers, optimal hP2YR affinity (IC, nM) was achieved with -linked glycosides of fucose (6.19) and lactose (1.88), and -linked glucose (5.30). Selected compounds were examined in mouse models of conditions known to be ameliorated by P2YR antagonists. Two glycoconjugates that lacked a piperidine moiety, -linked glucose derivative and the isomeric -linked glucose derivative , were protective in a mouse model of allergic asthma. Piperidine-containing glucose conjugate of intermediate linker length and corresponding glucuronide (MRS4866) protected against neuropathic pain. Thus, glycoconjugation of a known antagonist scaffold has produced less hydrophobic P2YR antagonists having substantial in vitro and in vivo activity.