Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y <sub>14</sub> Receptor Antagonists
Zhiwei Wen, Asmita Pramanik, Sarah A. Lewicki, Kwan‐Young Jung, Zhan‐Guo Gao, John C.R. Randle, Chunxia Cronin, Zhoumou Chen, Luigino Antonio Giancotti, Gregory S. Whitehead, Bruce T. Liang, Sylvie Breton, Daniela Salvemini, Donald N. Cook, Kenneth A. Jacobson
Abstract
P2Y 14 receptor (P2Y 14 R) is activated by extracellular UDP-glucose, a damage-associated molecular pattern that promotes inflammation in the kidney, lung, fat tissue, and elsewhere. Thus, selective P2Y 14 R antagonists are potentially useful for inflammatory and metabolic diseases. The piperidine ring size of potent, competitive P2Y 14 R antagonist (4-phenyl-2-naphthoic acid derivative) PPTN 1 was varied from 4- to 8-membered rings, with bridging/functional substitution. 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 or hydroxy/methoxy groups. The alicyclic amines displayed structural preference. An α-hydroxyl group increased the affinity of 4-(4-((1 R,5 S,6 r )-6-hydroxy-3-azabicyclo[3.1.1]heptan-6-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-naphthoic acid 15 (MRS4833) compared to 14 by 89-fold. 15 but not its double prodrug 50 reduced airway eosinophilia in a protease-mediated asthma model, and orally administered 15 and prodrugs reversed chronic neuropathic pain (mouse CCI model). Thus, we identified novel drug leads having in vivo efficacy.