Synthesis and structure-activity relationship of uracil nucleotide derivatives towards the identification of human P2Y6 receptor antagonists

Diana Meltzer, Ophir Ethan, Guillaume Arguin, Yael Nadel, Ortal Danino, Joanna Lecka, Jean Sévigny, Fernand Pierre Gendron, Bilha Fischer

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)5764-5773
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number17
DOIs
StatePublished - 1 Sep 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

  • Antagonist
  • Human P2Y receptor
  • Structure-activity relationship (SAR)
  • UDP

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