4-Benzylamino-1-chloro-6-substituted phthalazines: synthesis and inhibitory activity toward phosphodiesterase 5.
We synthesized various 4-benzylamino-1-chloro-6-substituted phthalazines (15) and 4-benzylamino-1-chloro-7-substituted phthalazines (16) and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) purified from porcine platelets. The PDE5-inhibitory activities of 15 were greater than those of the isomers (16). The preferred substituent at the 4-position of phthalazine was a (3-chloro-4-methoxybenzyl)amino group, and those at the 6-position were cyano, nitro, and trifluoromethyl groups. Compounds 15a (IC50 = 4.8 nM), 15f (3.5 nM), and 15i (5.3 nM) were more potent inhibitors than E4021 (8.6 nM). Compounds 15a and 15f also showed vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The EC50 values for vasorelaxant action of 15a, 15f, and E4021 were 150, 160, and 980 nM, respectively. These results show that novel PDE5 inhibitors possessing a potent vasorelaxant effect may exist among phthalazine derivatives.
Tsukuba Research Laboratories, Eisai Company, Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
N
N
Watanabe
Y
Y
Kabasawa
Y
Y
Takase
M
M
Matsukura
K
K
Miyazaki
H
H
Ishihara
K
K
Kodama
H
H
Adachi
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D015237:Dinoprost / Q000494:pharmacology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013552:Swine; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology
C114179:1-chloro-4-((3-chloro-4-methoxybenzyl)amino)-6-phthalazinecarbonitrile; C114180:1-chloro-4-((3-chloro-4-methoxybenzyl-)amino)-6-nitrophthalazine; 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