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:https://doi.org/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

Bar-Ilan University

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

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

Keywords

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

All Science Journal Classification (ASJC) codes

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmaceutical Science
Organic Chemistry

UN SDGs

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

Access to Document

https://doi.org/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.",

keywords = "Antagonist, Human P2Y receptor, Structure-activity relationship (SAR), UDP",

author = "Diana Meltzer and Ophir Ethan and Guillaume Arguin and Yael Nadel and Ortal Danino and Joanna Lecka and Jean S{\'e}vigny and Gendron, {Fernand Pierre} and Bilha Fischer",

year = "2015",

month = sep,

day = "1",

doi = "https://doi.org/10.1016/j.bmc.2015.07.004",

language = "الإنجليزيّة",

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TY - JOUR

T1 - Synthesis and structure-activity relationship of uracil nucleotide derivatives towards the identification of human P2Y6 receptor antagonists

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

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

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.

KW - Antagonist

KW - Human P2Y receptor

KW - Structure-activity relationship (SAR)

KW - UDP

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JO - Bioorganic and Medicinal Chemistry

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