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

• Published in: Journal of medicinal chemistry Vol. 66; no. 13; pp. 9076 - 9094
• Main Authors: Wen, Zhiwei, Pramanik, Asmita, Lewicki, Sarah A, Jung, Young-Hwan, Gao, Zhan-Guo, Randle, John C R, Cronin, Chunxia, Chen, Zhoumou, Giancotti, Luigino A, Whitehead, Gregory S, Liang, Bruce T, Breton, Sylvie, Salvemini, Daniela, Cook, Donald N, Jacobson, Kenneth A
• Format: Journal Article
• Language: English
• Published: United States 13.07.2023
• Subjects: Animals; Mice; Naphthalenes - pharmacology; Naphthalenes - therapeutic use; Receptors, Purinergic P2 - metabolism; Uridine Diphosphate Glucose - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00664

P2Y receptor (P2Y 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 R antagonists are potentially useful for inflammatory and metabolic diseases. The piperidine ring size of potent, competitive P2Y R antagonist (4-phenyl-2-naphthoic acid derivative) PPTN was varied from 4- to 8-membered rings, with bridging/functional substitution. Conformationally and sterically modified isosteres included -containing spirocyclic ( - ), fused ( - ), and bridged ( , ) or large ( - ) 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 ,5 ,6 )-6-hydroxy-3-azabicyclo[3.1.1]heptan-6-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (MRS4833) compared to by 89-fold. but not its double prodrug reduced airway eosinophilia in a protease-mediated asthma model, and orally administered and prodrugs reversed chronic neuropathic pain (mouse CCI model). Thus, we identified novel drug leads having in vivo efficacy.