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Papers of the Week

Papers: 24 Jun 2023 - 30 Jun 2023

Basic Science

Animal Studies, Molecular/Cellular, Pharmacology/Drug Development

Neuropathic Pain

2023 Jun 29

J Med Chem


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


Wen Z, Pramanik A, Lewicki SA, Jung YH, Gao ZG, Randle JCR, Cronin C, Chen Z, Giancotti LA, Whitehead GS, Liang BT, Breton S, Salvemini D, Cook DN, Jacobson KA


P2Y receptor (P2YR) is activated by extracellular UDP-glucose, a damage-associated molecular pattern that promotes inflammation in the kidney, lung, fat tissue, and elsewhere. Thus, selective P2YR antagonists are potentially useful for inflammatory and metabolic diseases. The piperidine ring size of potent, competitive P2YR 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.