Synthesis and Pharmacological Evaluations of Sildenafil Analogues for Treatment of Erectile Dysfunction.

The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-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 analogs, characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moieties, were prepd. by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogs showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compds. caused concn.-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogs potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. I exhibited great pEC50 value in corpus cavernosum, and two other compds. in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogs were significantly more lipophilic than sildenafil, these compds. may offer a new lead for development of new sildenafil analogs.