Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y₁₄ 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 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-((1R,5S,6r)-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.

Discovery of N-Substituted Acetamide Derivatives as Promising P2Y14R Antagonists Using Molecular Hybridization Based on Crystallographic Overlay

“…Specially, Jacobson’s group focused on sterically constrained, bridged piperidine modifications in this zwitterionic naphthalene series, and many successful examples were synthesized through an “escaping from flatland” strategy; compound 8 is one of the series (Figure ). , …”

Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment

“…Currently, the reported P2Y 14 receptor antagonists comprise compounds (Figure A, 2 – 6 ) derived from lead compound PPTN (Figure A, 1 ) and compounds (Figure B, 7 – 9 ) identified through virtual screening. The PPTN-derived compounds include: 2-naphthalic acid derivatives (Figure , 1 ), 3-alkynyl benzoic acid derivatives (Figure , 2 ), 3-triazole benzoic acid derivatives (Figure , 3 ), 3-amide benzoic acid derivatives (Figure , 4 , 5 ), and 5-amide-1 H -pyrazole-3-carboxyl derivatives (Figure , 6 ). ,, Compound 9 (Figure , 9 ) was designed and optimized based on compounds 7 and 8 (Figure , 7 , 8 ) obtained through virtual screening of the hP2Y 14 receptor. , However, the limited number of P2Y 14 receptor antagonists, particularly those with novel scaffolds, significantly hinders the exploration of the P2Y 14 receptor as a potential drug target. Furthermore, none of the P2Y 14 receptor antagonists are approved by the Food and Drug Administration (FDA) or are undergoing Phase I clinical trials.…”