title: Enzymological and pharmacological profile of T-0156, a potent and selective phosphodiesterase type 5 inhibitor.
abstract: The enzymological and pharmacological properties of 2-(2-Methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T-0156), a new phosphodiesterase type 5 inhibitor, were studied in vitro and in vivo. The inhibitory effects of T-0156 on six phosphodiesterase isozymes isolated from canine tissues were investigated. T-0156 specifically inhibited the hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase type 5, at low concentration (IC(50)=0.23 nM), in a competitive manner. T-0156 also inhibited phosphodiesterase type 6 with IC(50) value of 56 nM, which was 240-fold higher than that for inhibition of phosphodiesterase type 5. T-0156 had low potencies against phosphodiesterase types 1, 2, 3, and 4 (IC(50)>10 microM). In the isolated rabbit corpus cavernosum, T-0156 at 10 and 100 nM increased cGMP levels (100 nM T-0156-treated: 6.0+/-1.5 pmol/mg protein, vehicle-treated: 1.1+/-0.4 pmol/mg protein, P<0.05), causing relaxation of the tissue. T-0156 at 1 to 100 nM potentiated the electrical field stimulation-induced relaxation in the isolated rabbit corpus cavernosum in a concentration-dependent manner (100 nM T-0156-treated: 76.9+/-19.8%, vehicle-treated: 12.3+/-10.1%, P<0.05). Intraduodenal administration of T-0156 at 100 to 1000 microg/kg potentiated the pelvic nerve stimulation-induced tumescence in anesthetized dogs (1000 microg/kg T-0156-treated: 279.0+/-38.4%, vehicle-treated: 9.8+/-4.5%, P<0.05). These results suggested that T-0156 enhanced the nitric oxide (NO)/cGMP pathway, probably through blockade of phosphodiesterase type 5 in vitro and in vivo experimental conditions. The present study clearly showed that T-0156 is a potent and highly selective phosphodiesterase type 5 inhibitor, which is a useful tool for pharmacological studies in vitro and in vivo.
authors.affiliation: Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda, Saitama, Japan. mochida@tanabe.co.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochida
authors.forename: Michino
authors.initials: M
authors.lastname: Takagi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Inoue
authors.forename: Tsunehisa
authors.initials: T
authors.lastname: Noto
authors.forename: Koji
authors.initials: K
authors.lastname: Yano
authors.forename: Kotomi
authors.initials: K
authors.lastname: Fujishige
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Keizo
authors.initials: K
authors.lastname: Yuasa
authors.forename: Jun
authors.initials: J
authors.lastname: Kotera
authors.forename: Kenji
authors.initials: K
authors.lastname: Omori
authors.forename: Kohei
authors.initials: K
authors.lastname: Kikkawa
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000758:Anesthesia; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009287:Naphthyridines / Q000494:pharmacology*; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay
chemical_list: D007527:Isoenzymes; D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; C473961:T0156; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP