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

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

  • J Med Chem. 2023 Jul 13;66(13):9076-9094. doi: 10.1021/acs.jmedchem.3c00664.
Zhiwei Wen 1,  Asmita Pramanik 1,  Sarah A Lewicki 1,  Young-Hwan Jung 1,  Zhan-Guo Gao 1,  John C R Randle 2,  Chunxia Cronin 3,  Zhoumou Chen 4,  Luigino A Giancotti 4,  Gregory S Whitehead 5,  Bruce T Liang 3,  Sylvie Breton 6,  Daniela Salvemini 4,  Donald N Cook 5,  Kenneth A Jacobson 1
Affiliations

Affiliations

  • 1 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 2 Random Walk Ventures, LLC, 108 Lincoln Street Unit 6B, Boston, Massachusetts 02111, United States.
  • 3 Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, Connecticut 06030, United States.
  • 4 Department of Pharmacology and Physiology and the Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, Missouri 63104, United States.
  • 5 Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, United States.
  • 6 Centre de Recherche du CHU de Québec, Département d'Obstétrique, de Gynécologie et Reproduction, Faculté de Médecine, Université Laval, Laval, Québec G1V 4G2, Canada.
PMID: 37382926 DOI: 10.1021/acs.jmedchem.3c00664
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.

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