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

doi:10.1016/j.bmc.2015.07.004

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

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

21 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 language	English
Pages (from-to)	5764-5773
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	17
DOIs	https://doi.org/10.1016/j.bmc.2015.07.004
State	Published - 1 Sep 2015

Bibliographical note

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

Funding

This research was supported by Crohn’s and Colitis Foundation of Canada Grant in Aid of Research (2009–2012) and a CIHR operating Grant ( MOP-286567 ) to F.P.G, and the Beck Foundation to B.F. (Crohn’s disease grant).

Funders	Funder number
Beck Foundation
Crohn's and Colitis Foundation of Canada
Canadian Institutes of Health Research	MOP-286567

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmc.2015.07.004

Cite this

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

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.",

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AU - Meltzer, Diana

AU - Ethan, Ophir

AU - Arguin, Guillaume

AU - Nadel, Yael

AU - Danino, Ortal

AU - Lecka, Joanna

AU - Sévigny, Jean

AU - Gendron, Fernand Pierre

AU - Fischer, Bilha

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AB - 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.

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