Exploration of Alternative Scaffolds for P2Y<sub>14</sub> Receptor Antagonists Containing a Biaryl Core.
Jung YH, Yu J, Wen Z, Salmaso V, Karcz TP, Phung NB, Chen Z, Duca S, Bennett JM, Dudas S, Salvemini D, Gao ZG, Cook DN, Jacobson KA.
Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y<sub>14</sub> receptor (P2Y<sub>14</sub>R) antagonists were synthesized, and affinity was measured in P2Y<sub>14</sub>R-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 <i>m</i>-benzoic acid core (<b>25</b>) provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2Y<sub>14</sub>R 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 <b>1</b>, e.g., quinuclidine <b>17</b> (MRS4608, IC<sub>50</sub> ≈ 20 nM at hP2Y<sub>14</sub>R/mP2Y<sub>14</sub>R), or of triazole <b>2</b>, preserved affinity. Potent antagonists <b>1</b>, <b>7a</b>, <b>17</b>, and <b>23</b> (10 mg/kg) protected in an ovalbumin/<i>Aspergillus</i> mouse asthma model, and PEG conjugate <b>12</b> reduced chronic pain. Thus, we expanded P2Y<sub>14</sub>R antagonist structure-activity relationship, introducing diverse physical-chemical properties.