High-Affinity, Non-Nucleotide-Derived Competitive Antagonists of Platelet P2Y12 Receptors
High-Affinity, Non-Nucleotide-Derived Competitive Antagonists of Platelet P2Y12 Receptors
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DOI：
10.1021/jm9003297
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发表时间：
2009-06-25
影响因子：
7.3
通讯作者：
Mueller, Christa E.
中科院分区：
文献类型：
--
作者：
Baqi, Younis;Atzler, Kerstin;Mueller, Christa E.
合成了与中等效力的非选择性P2 Y（12）受体拮抗剂活性蓝2（6）相关的蒽醌衍生物，并对P2 Y（12）受体亲和力进行了优化。采用人血小板膜和P2 Y（12）受体选择性拮抗剂放射性配体[H-3]2-丙硫代腺苷-5 '-腺苷酸（1，1-二氯-1-膦酰基甲基-1-膦酰基）酐（[H-3]PSB-0413）进行放射性配体结合试验，用于化合物检测。1-氨基-2-磺基蒽醌衍生物在4-位上具有（对苯氨基）苯胺基取代，并且在苯胺环的间位上具有额外的酸性官能团，显示出高的P2 Y（12）受体亲和力。这些新的蒽醌衍生物可以通过最近发展的铜（0）催化的1-氨基-4-溴蒽醌衍生物与苯胺在磷酸盐缓冲液中在微波辐射下的Ullmann偶联反应来获得。最有效化合物的Ki值分别为24.9 nM（1-氨基-4-[4-苯基氨基-3-磺基苯基氨基]-9，10-二氧代-9，10-二氢蒽-2-磺酸盐，PSB-0739，39）和21.0 nM（1-氨基-4-[4-苯基氨基-3-羧基苯基氨基]-9，10-二氧代-9，10-二氢蒽-2-磺酸盐，PSB-0702，41）。1-氨基-2-磺基-4-苯胺基蒽醌衍生物似乎无细胞毒性，如在两种人细胞系（黑色素瘤和星形细胞瘤）中所选衍生物所示。化合物39和41代表了用于开发抗血栓药物的新的先导结构。
Anthraquinone derivatives related to the moderately potent, nonselective P2Y(12) receptor antagonist reactive blue 2 (6) have been synthesized and optimized with respect to P2Y(12) receptor affinity. A radioligand binding assay utilizing human blood platelet membranes and the P2Y(12) receptor-selective antagonist radioligand [H-3]2-propylthioadenosine-5'-adenylic acid (1,1-dichloro-1-phosphonomethyl-1-phosphonyl) anhydride ([H-3]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 P2Y(12) 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 K-i values of 24.9 nM (1-amino-4-[4-phenylamino-3-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, PSB-0739, 39), and 2 1.0 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.