Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y₁₄ Receptor Antagonists

P2Y(14) receptor (P2Y(14)R) is activatedby extracellularUDP-glucose, a damage-associated molecular pattern that promotes inflammationin the kidney, lung, fat tissue, and elsewhere. Thus, selective P2Y(14)R antagonists are potentially useful for inflammatory andmetabolic diseases. The piperidine ring size of potent, competitiveP2Y(14)R antagonist (4-phenyl-2-naphthoic acid derivative)PPTN 1 was varied from 4- to 8-membered rings, with bridging/functionalsubstitution. Conformationally and sterically modified isosteres included N-containing spirocyclic (6-9), fused (11-13), and bridged (14, 15) or large (16-20) ring systems, either saturated or containing alkene orhydroxy/methoxy groups. The alicyclic amines displayed structuralpreference. An & alpha;-hydroxyl group increased the affinity of 4-(4-((1R,5S,6r)-6-hydroxy-3-azabicyclo[3.1.1]heptan-6-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-naphthoicacid 15 (MRS4833) compared to 14 by 89-fold. 15 but not its double prodrug 50 reduced airwayeosinophilia in a protease-mediated asthma model, and orally administered 15 and prodrugs reversed chronic neuropathic pain (mouse CCImodel). Thus, we identified novel drug leads having in vivo efficacy.