Papers of the Week

Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y receptor (P2YR) antagonists were synthesized, and affinity was measured in P2YR-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central -benzoic acid core () provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2YR region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist , e.g., quinuclidine (MRS4608, IC ≈ 20 nM at hP2YR/mP2YR), or of triazole , preserved affinity. Potent antagonists , , , and (10 mg/kg) protected in an ovalbumin/ mouse asthma model, and PEG conjugate reduced chronic pain. Thus, we expanded P2YR antagonist structure-activity relationship, introducing diverse physical-chemical properties.