Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y ₁₄ Receptor Antagonists

Abstract

P2Y₁₄ receptor (P2Y₁₄R) is activated by extracellular UDP-glucose, a damage-associated molecular pattern that promotes inflammation in the kidney, lung, fat tissue, and elsewhere. Thus, selective P2Y₁₄R antagonists are potentially useful for inflammatory and metabolic diseases. The piperidine ring size of potent, competitive P2Y₁₄R antagonist (4-phenyl-2-naphthoic acid derivative) PPTN <b>1</b> was varied from 4- to 8-membered rings, with bridging/functional substitution. Conformationally and sterically modified isosteres included <i>N</i>-containing spirocyclic (<b>6</b>-<b>9</b>), fused (<b>11</b>-<b>13</b>), and bridged (<b>14</b>, <b>15</b>) or large (<b>16</b>-<b>20</b>) ring systems, either saturated or containing alkene or hydroxy/methoxy groups. The alicyclic amines displayed structural preference. An α-hydroxyl group increased the affinity of 4-(4-((1<i>R</i>,5<i>S</i>,6<i>r</i>)-6-hydroxy-3-azabicyclo[3.1.1]heptan-6-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-naphthoic acid <b>15</b> (MRS4833) compared to <b>14</b> by 89-fold. <b>15</b> but not its double prodrug <b>50</b> reduced airway eosinophilia in a protease-mediated asthma model, and orally administered <b>15</b> and prodrugs reversed chronic neuropathic pain (mouse CCI model). Thus, we identified novel drug leads having in vivo efficacy.