High-affinity, non-nucleotide-derived competitive antagonists of platelet P2Y12 receptors

Younis Baqi, Kerstin Atzler, Meryem Köse, Markus Glänzel, Christa E. Müller

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Anthraquinone derivatives related to the moderately potent, nonselective P2Y12 receptor antagonist reactive blue 2 (6) have been synthesized and optimized with respect to P2Y12 receptor affinity. A radioligand binding assay utilizing human blood platelet membranes and the P2Y12 receptor-selective antagonist radioligand [3H]2-propylthioadenosine- 5′-adenylic acid (1,1-dichloro-1-phosphonomethyl-1-phosphonyl) anhydride ([3H]PSB-0413) was applied for compound testing. 1-Amino-2- sulfoanthraquinone derivatives bearing a (p-phenylamino) anilino substitution in the 4-position and an additional acidic function in the meta-position of the aniline ring showed high P2Y12 receptor affinity. These new anthraquinone derivatives became accessible by a recently developed copper(0)-catalyzed Ullmann coupling reaction of 1-amino-4-bromoanthraquinone derivatives with anilines in phosphate buffer under microwave irradiation. The most potent compounds exhibited Ki values of 24.9 nM (1-amino-4-[4-phenylamino-3-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene- 2-sulfonate, PSB-0739, 39), and 21.0 nM (1-amino-4-[4-phenylamino-3- carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, PSB-0702, 41), respectively. 1-Amino-2-sulfo-4-anilinoanthraquinone derivatives appeared to be noncytotoxic, as shown for selected derivatives at two human cell lines (melanoma and astrocytoma). Compounds 39 and 41 represent new lead structures for the development of antithrombotic drugs.

Original languageEnglish
Pages (from-to)3784-3793
Number of pages10
JournalJournal of Medicinal Chemistry
Volume52
Issue number12
DOIs
Publication statusPublished - Jun 25 2009

Fingerprint

Purinergic P2Y Receptor Antagonists
Anthraquinones
Cibacron Blue F 3GA
Aniline Compounds
Radioligand Assay
Astrocytoma
Microwaves
Copper
Melanoma
Buffers
Blood Platelets
Phosphates
Cell Line
Membranes
Pharmaceutical Preparations
PSB-0413

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

High-affinity, non-nucleotide-derived competitive antagonists of platelet P2Y12 receptors. / Baqi, Younis; Atzler, Kerstin; Köse, Meryem; Glänzel, Markus; Müller, Christa E.

In: Journal of Medicinal Chemistry, Vol. 52, No. 12, 25.06.2009, p. 3784-3793.

Research output: Contribution to journalArticle

Baqi, Younis ; Atzler, Kerstin ; Köse, Meryem ; Glänzel, Markus ; Müller, Christa E. / High-affinity, non-nucleotide-derived competitive antagonists of platelet P2Y12 receptors. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 12. pp. 3784-3793.
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abstract = "Anthraquinone derivatives related to the moderately potent, nonselective P2Y12 receptor antagonist reactive blue 2 (6) have been synthesized and optimized with respect to P2Y12 receptor affinity. A radioligand binding assay utilizing human blood platelet membranes and the P2Y12 receptor-selective antagonist radioligand [3H]2-propylthioadenosine- 5′-adenylic acid (1,1-dichloro-1-phosphonomethyl-1-phosphonyl) anhydride ([3H]PSB-0413) was applied for compound testing. 1-Amino-2- sulfoanthraquinone derivatives bearing a (p-phenylamino) anilino substitution in the 4-position and an additional acidic function in the meta-position of the aniline ring showed high P2Y12 receptor affinity. These new anthraquinone derivatives became accessible by a recently developed copper(0)-catalyzed Ullmann coupling reaction of 1-amino-4-bromoanthraquinone derivatives with anilines in phosphate buffer under microwave irradiation. The most potent compounds exhibited Ki values of 24.9 nM (1-amino-4-[4-phenylamino-3-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene- 2-sulfonate, PSB-0739, 39), and 21.0 nM (1-amino-4-[4-phenylamino-3- carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, PSB-0702, 41), respectively. 1-Amino-2-sulfo-4-anilinoanthraquinone derivatives appeared to be noncytotoxic, as shown for selected derivatives at two human cell lines (melanoma and astrocytoma). Compounds 39 and 41 represent new lead structures for the development of antithrombotic drugs.",
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