Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl antagonists of the P2Y14 receptor (P2Y14R) were synthesized and tested for affinity in P2Y14R-expressing CHO cells by flow cytometry. Given this series’ low water solubility, various polyethylene glycol derivatives of a distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Reversal of a previously identified 1,2,3-triazole attached to the central m-benzoic acid core in 25 provided moderate affinity, but not indole and benzimidazole substitution of the aryl-triazole moiety. The corresponding region of P2Y14R is predicted by homology modeling as a deep and sterically-limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic substituted piperidine ring derivatives of naphthalene antagonist 1, e.g. quinuclidine 17 (MRS4608, IC50 ~20 nM at hP2Y14R and mP2Y14R), or of triazole 2, e.g. quinuclidine 18 (MRS4619, IC50 105 nM at hP2Y14R), preserved affinity well compared to many other modifications of PPTN. The t1/2 of compounds 17 and 18 were 5.1 and 4.6 h, respectively (1 mg/kg, i.p.). Potent analogues were protective in an in vivo ovalbumin/Aspergillus asthma model. Thus, we expanded P2Y14R antagonist SAR, introducing diverse physical-chemical properties and demonstrate their activity in an asthma model.

Exploration of alternative scaffolds for P2Y14 receptor antagonists containing a biaryl core

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.