title: Potent inhibition of human phosphodiesterase-5 by icariin derivatives.
abstract: Plant extracts traditionally used for male impotence (Tribulus terrestris, Ferula hermonis, Epimedium brevicornum, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. Only E. brevicornum extract (80% inhibition at 50 microg/mL) and its active principle icariin (1) (IC50 5.9 microM) were active. To improve its inhibitory activity, 1 was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin (5), where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC50 very close to that of sildenafil (IC50 75 vs 74 nM). Thus, 5 was 80 times more potent than 1, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make compound 5 a promising candidate for further development.
authors.affiliation: Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy. mario.dellagli@unimi.it
authors.forename: Mario
authors.initials: M
authors.lastname: Dell'Agli
authors.forename: Germana V
authors.initials: GV
authors.lastname: Galli
authors.forename: Esther
authors.initials: E
authors.lastname: Dal Cero
authors.forename: Federica
authors.initials: F
authors.lastname: Belluti
authors.forename: Riccardo
authors.initials: R
authors.lastname: Matera
authors.forename: Elisa
authors.initials: E
authors.lastname: Zironi
authors.forename: Giampiero
authors.initials: G
authors.lastname: Pagliuca
authors.forename: Enrica
authors.initials: E
authors.lastname: Bosisio
mesh_terms: D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors; D034181:Epimedium / Q000737:chemistry; D007172:Erectile Dysfunction / Q000188:drug therapy; D005309:Ferula / Q000737:chemistry; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000494:pharmacology*; D032444:Tribulus / Q000737:chemistry
chemical_list: D005419:Flavonoids; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010936:Plant Extracts; D011687:Purines; D013450:Sulfones; C532608:3,7-bis(2-hydroxyethyl)icaritin; D000068677:Sildenafil Citrate; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C056599:icariin