Synthesis and structure–activity relationship of uracil nucleotide derivatives towards the identification of human P2Y 6 receptor antagonists
| Autor: | Ophir Ethan, Joanna Lecka, Diana Meltzer, Ortal Danino, Fernand-Pierre Gendron, Bilha Fischer, Jean Sévigny, Yael Nadel, Guillaume Arguin |
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| Rok vydání: | 2015 |
| Předmět: |
Molecular Structure
Receptors Purinergic P2 Uracil Nucleotides Stereochemistry Organic Chemistry Clinical Biochemistry Antagonist Pharmaceutical Science Uracil Biochemistry 3. Good health Structure-Activity Relationship chemistry.chemical_compound chemistry Drug Discovery Ribose Humans Molecular Medicine Structure–activity relationship Moiety Receptor Molecular Biology IC50 Uracil nucleotide |
| Zdroj: | Bioorganic & Medicinal Chemistry. 23:5764-5773 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2015.07.004 |
| Popis: | P2Y6 receptor (P2Y6-R) is involved in various physiological and pathophysiological events. With a view to set rules for the design of UDP-based reversible P2Y6-R antagonists as potential drugs, we established structure-activity relationship of UDP analogues, bearing modifications at the uracil ring, ribose moiety, and the phosphate chain. For instance, C5-phenyl- or 3-NMe-uridine-5'-α,β-methylene-diphosphonate, 16 and 23, or lack of 2'-OH, in 12-15, resulted in loss of both agonist and antagonist activity toward hP2Y6-R. However, uridylyl phosphosulfate, 19, selectively inhibited hP2Y6-R (IC50 112 μM) versus P2Y2/4-Rs. In summary, we have established a comprehensive SAR for hP2Y6-R ligands towards the development of hP2Y6-R antagonists. |
| Databáze: | OpenAIRE |
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