Author: Whitehead, Gregory S ; Jung, Young-Hwan ; Jacobson, Kenneth A ; Randle, John C R ; Pramanik, Asmita ; Breton, Sylvie ; Cronin, Chunxia ; Wen, Zhiwei ; Giancotti, Luigino A ; Gao, Zhan-Guo ; Cook, Donald N ; Liang, Bruce T ; Salvemini, Daniela ; Lewicki, Sarah A ; Chen, Zhoumou

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.

Journal of Medicinal Chemistry

Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y14 Receptor Antagonists

Author: Jung, Young-Hwan ; Salvemini, Daniela ; Pramanik, Asmita ; Randle, John C. R. ; Whitehead, Gregory S. ; Jacobson, Kenneth A. ; Wen, Zhiwei ; Cronin, Chunxia ; Giancotti, Luigino A. ; Gao, Zhan-Guo ; Breton, Sylvie ; Liang, Bruce T. ; Lewicki, Sarah A. ; Cook, Donald N. ; Chen, Zhoumou

P2Y14 receptor (P2Y₁₄R) is activated by extracellular UDP-glucose, a damage-associated mol. 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.Fifteen 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Preclinical	United States	National Institute of Diabetes & Digestive & Kidney Diseases	29 Jun 2023
Metabolic Diseases	Preclinical	United States	National Institute of Diabetes & Digestive & Kidney Diseases	29 Jun 2023

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