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Bioorg Med Chem. 2015 Sep 1;23(17):5764-73. doi: 10.1016/j.bmc.2015.07.004. Epub 2015 Jul 11.

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

Author information

1
Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
2
Department of Anatomy and Cellular Biology, Université de Sherbrooke, rue Jean-Mignault, Sherbrooke 3201, QC, Canada.
3
Centre de Recherche en Rhumatologie et Immunologie, Université Laval, Québec, QC, Canada.
4
Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel. Electronic address: bilha.fischer@biu.ac.il.

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.

KEYWORDS:

Antagonist; Human P2Y(6) receptor; Structure–activity relationship (SAR); UDP

PMID:
26233801
DOI:
10.1016/j.bmc.2015.07.004
[Indexed for MEDLINE]

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