title: Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction.
abstract: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
authors.forename: Haroldo A
authors.initials: HA
authors.lastname: Flores Toque
authors.forename: Fernanda B M
authors.initials: FB
authors.lastname: Priviero
authors.forename: Cleber E
authors.initials: CE
authors.lastname: Teixeira
authors.forename: Elisa
authors.initials: E
authors.lastname: Perissutti
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Fiorino
authors.forename: Beatrice
authors.initials: B
authors.lastname: Severino
authors.forename: Francesco
authors.initials: F
authors.lastname: Frecentese
authors.forename: Raquel
authors.initials: R
authors.lastname: Lorenzetti
authors.forename: Juliana S
authors.initials: JS
authors.lastname: Baracat
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Santagada
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Caliendo
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
authors.forename: Gilberto
authors.initials: G
authors.lastname: De Nucci
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000502:physiology; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000187:drug effects / Q000502:physiology; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D000068677:Sildenafil Citrate; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C529820:5-(2-ethoxy-5-(4-(4-fluorophenyl)piperazinylsulfonyl)phenyl)-1-methyl-3N-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; C529822:5-(2-ethoxy-5-(N-acetic acid,N'-5-(2-ethoxy-5-sulfonyl)phenyl)-1-methyl-3-N-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one-ethylenediaminesulfonylphenyl)-1-methyl-3-N-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; C529821:5-(2-ethoxy-5-(N-phenylethylenediaminesulfonyl)phenyl)-1-methyl-3-N-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D011743:Pyrimidines; D013450:Sulfones; D000068677:Sildenafil Citrate