Chimeras Derived from a P2Y 14 Receptor Antagonist and UDP-Sugar Agonists for Potential Treatment of Inflammation.

Autor: Wen Z; 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., Pramanik A; 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., Lewicki SA; 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., Jung YH; 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., Gao ZG; 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., Randle JCR; Random Walk Ventures, LLC, 108 Lincoln Street Unit 6B, Boston, Massachusetts 02111, United States., Breton S; Centre de Recherche du CHU de Québec, Département d'Obstétrique, de Gynécologie et Reproduction, Faculté de Médecine, Université Laval, Laval, Québec G1 V 4G2, Canada., Chen Z; 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., Whitehead GS; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, United States., Salvemini D; 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., Cook DN; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, United States., Jacobson KA; 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.
Jazyk: angličtina
Zdroj: ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 Sep 26; Vol. 7 (10), pp. 3255-3278. Date of Electronic Publication: 2024 Sep 26 (Print Publication: 2024).
DOI: 10.1021/acsptsci.4c00489
Abstrakt: Tethered glycoconjugates of a naphthalene- and piperidine-containing antagonist of the P2Y 14 receptor (PPTN) were synthesized, and their nM receptor binding affinity was determined using a fluorescent tracer in hP2Y 14 R-expressing whole CHO cells. The rationale for preparing mono- and disaccharide conjugates of the antagonists was to explore the receptor binding site, which we know recognizes a glucose moiety on the native agonist (UDP-glucose), as well as enhance aqueous solubility and pharmacokinetics, including kidney excretion to potentially counteract sterile inflammation. Glycoconjugates with varied linker length, including PEG chains, were compared in hP2Y 14 R binding, suggesting that an optimal affinity (IC 50 , nM) in the piperidine series was achieved for triazolyl N -linked glucose conjugates having one ( 8a , MRS4872, 3.21) or two ( 7a , MRS4865, 2.40) methylene spacers. In comparison of different carbohydrate conjugates lacking a piperidine moiety but containing triazole spacers, optimal hP2Y 14 R affinity (IC 50 , nM) was achieved with N -linked glycosides of fucose 10f (6.19) and lactose 10h (1.88), and C -linked glucose 11a (5.30). Selected compounds were examined in mouse models of conditions known to be ameliorated by P2Y 14 R antagonists. Two glycoconjugates that lacked a piperidine moiety, N -linked glucose derivative 10a and the isomeric C -linked glucose derivative 11a , were protective in a mouse model of allergic asthma. Piperidine-containing glucose conjugate 7a of intermediate linker length and corresponding glucuronide 7b (MRS4866) protected against neuropathic pain. Thus, glycoconjugation of a known antagonist scaffold has produced less hydrophobic P2Y 14 R antagonists having substantial in vitro and in vivo activity.
Competing Interests: The authors declare no competing financial interest.
(© 2024 American Chemical Society.)
Databáze: MEDLINE
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