Flores Toque Haroldo A, Priviero Fernanda B M, Teixeira Cleber E, Perissutti Elisa, Fiorino Ferdinando, Severino Beatrice, Frecentese Francesco, Lorenzetti Raquel, Baracat Juliana S, Santagada Vincenzo, Caliendo Giuseppe, Antunes Edson, De Nucci Gilberto
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
J Med Chem. 2008 May 8;51(9):2807-15. doi: 10.1021/jm701400r. Epub 2008 Apr 5.
The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.
5-[2-乙氧基-5-(4-甲基哌嗪-1-基磺酰基)苯基]-1-甲基-3-丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮,西地那非,是一种用于治疗阴茎勃起功能障碍的环磷酸鸟苷特异性磷酸二酯酶-5(PDE5)抑制剂。为了寻找更有效和更具选择性的PDE5抑制剂,通过传统合成方法和微波辅助合成方法制备了以5'位磺酰基上存在新型N-4-取代哌嗪或乙二胺部分为特征的新型西地那非类似物(6a-v),并在兔离体主动脉和海绵体中进行了测试。与西地那非类似,几种类似物的IC50值在纳摩尔范围内。在体外研究中,所有测试化合物在兔离体主动脉和海绵体中均引起浓度依赖性舒张。所有西地那非类似物均增强了内皮完整的兔主动脉中一氧化氮依赖性血管舒张作用。化合物6f在海绵体中表现出很高的pEC50值,并且发现离体主动脉中的化合物6r和6u在抑制PDE5方面与西地那非一样有效。由于几种类似物的亲脂性明显高于西地那非,这些化合物可能为新型西地那非类似物的开发提供新的线索。