TY - JOUR
T1 - Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y14 Receptor Antagonists
AU - Wen, Zhiwei
AU - Pramanik, Asmita
AU - Lewicki, Sarah A.
AU - Jung, Young Hwan
AU - Gao, Zhan Guo
AU - Randle, John C.R.
AU - Cronin, Chunxia
AU - Chen, Zhoumou
AU - Giancotti, Luigino A.
AU - Whitehead, Gregory S.
AU - Liang, Bruce T.
AU - Breton, Sylvie
AU - Salvemini, Daniela
AU - Cook, Donald N.
AU - Jacobson, Kenneth A.
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/7/13
Y1 - 2023/7/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85164625288&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85164625288&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c00664
DO - 10.1021/acs.jmedchem.3c00664
M3 - Article
C2 - 37382926
AN - SCOPUS:85164625288
SN - 0022-2623
VL - 66
SP - 9076
EP - 9094
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 13
ER -