Synthesis and pharmacological evaluation of 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas as novel thromboxane A2 receptor antagonists
Synthesis and pharmacological evaluation of 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas as novel thromboxane A2 receptor antagonists
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DOI：
10.1016/j.ejmech.2013.04.033
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发表时间：
2013-07-01
影响因子：
6.7
通讯作者：
Pirotte, Bernard
中科院分区：
文献类型：
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作者：
Bambi-Nyanguile, Sylvie-Mireille;Hanson, Julien;Pirotte, Bernard
合成了一系列新的2-芳氧基/芳氨基-5-氰基苯磺酰脲类化合物，并对其作为血栓素A（2）受体（TP受体）拮抗剂进行了评价。使用功能药理学试验，包括测量特异性过表达单个TP α或TP β亚型的哺乳动物细胞系模型中细胞内钙动员的抑制。2-芳氨基-5-氰基苯磺酰脲对TP α和TP β的亲和力和/或功能活性与2-芳氧基-5-氰基苯磺酰脲几乎相同，但一些2-芳氧基取代的化合物对TP β的选择性高于TP α。发现几种化合物与2-芳氨基-5-硝基苯磺酰脲参比化合物BM-573一样有效，支持了硝基被氰基的生物电子等排取代是可耐受的观点。在使用TP受体激动剂U-46619作为前聚集剂的血小板聚集测定中证实了最有希望的分子的TP受体拮抗剂活性。（7 e、7 h和8h）被确定为进一步非临床药理学和毒理学研究的先导药物。(C)2013年Elsevier Masson SAS。All rights reserved.
New series of original 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas were synthesized and evaluated as thromboxane A(2) receptor (TP receptor) antagonists. A functional pharmacological test was used, which consisted of measuring the inhibition of intracellular calcium mobilization in a model of mammalian cell line that specifically over-expressed the individual TP alpha or TP beta isoforms. 2-Arylamino-5-cyanobenzenesulfonylureas exhibited virtually identical affinity and/or functional activity than 2-aryloxy-5-cyanobenzenesulfonylureas for both TP alpha and TP beta, but some 2-aryloxy-substituted compounds showed increased selectivity for TP beta relative to TP alpha. Several compounds were found to be as potent as the 2-arylamino-5-nitrobenzenesulfonylurea reference compound BM-573, supporting the view that the bioisosteric replacement of the nitro group by a cyano group was tolerated.TP receptor antagonist activity of the most promising molecules was confirmed in a platelet aggregation assay using the TP receptor agonist U-46619 as a proaggregant.Three compounds (7e, 7h and 8h) were identified as leads for further non-clinical pharmacological and toxicological studies. (C) 2013 Elsevier Masson SAS. All rights reserved.