title: 4-(3-Chloro-4-methoxybenzyl)aminophthalazines: synthesis and inhibitory activity toward phosphodiesterase 5.
abstract: We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthala zinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC(50) = 0.56 nM) with >1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC(50) = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 microg/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.
authors.affiliation: Tsukuba Research Laboratories, Eisai Company, Ltd., Tsukuba, Ibaraki, Japan. n5-watanabe@hhc.eisai.co.jp
authors.forename: N
authors.initials: N
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Adachi
authors.forename: Y
authors.initials: Y
authors.lastname: Takase
authors.forename: H
authors.initials: H
authors.lastname: Ozaki
authors.forename: M
authors.initials: M
authors.lastname: Matsukura
authors.forename: K
authors.initials: K
authors.lastname: Miyazaki
authors.forename: K
authors.initials: K
authors.lastname: Ishibashi
authors.forename: H
authors.initials: H
authors.lastname: Ishihara
authors.forename: K
authors.initials: K
authors.lastname: Kodama
authors.forename: M
authors.initials: M
authors.lastname: Nishino
authors.forename: M
authors.initials: M
authors.lastname: Kakiki
authors.forename: Y
authors.initials: Y
authors.lastname: Kabasawa
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D015237:Dinoprost / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C411148:(4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino)-6-phthalazinecarbonitrile; D000959:Antihypertensive Agents; C091517:E 4021; D010726:Phosphodiesterase Inhibitors; D010793:Phthalazines; D010880:Piperidines; D011799:Quinazolines; D014665:Vasodilator Agents; D015237:Dinoprost; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat