4-Benzylamino-1-chloro-6-substituted Phthalazines:  Synthesis and Inhibitory Activity toward Phosphodiesterase 5

• Published in: Journal of medicinal chemistry Vol. 41; no. 18; pp. 3367 - 3372
• Main Authors: Watanabe, Nobuhisa, Kabasawa, Yasuhiro, Takase, Yasutaka, Matsukura, Masayuki, Miyazaki, Kazuki, Ishihara, Hiroki, Kodama, Kohtarou, Adachi, Hideyuki
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.08.1998; Amer Chemical Soc
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antianginal agents. Coronary vasodilator agents; Biological and medical sciences; Blood Platelets - enzymology; Cardiovascular system; Chemistry, Medicinal; Coronary Vessels - drug effects; Coronary Vessels - physiology; Cyclic Nucleotide Phosphodiesterases, Type 5; Dinoprost - pharmacology; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Muscle Contraction - drug effects; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; Phthalazines - chemical synthesis; Phthalazines - chemistry; Phthalazines - pharmacology; Piperidines - pharmacology; Quinazolines - pharmacology; Science & Technology; Swine; Vasodilator Agents - chemical synthesis; Vasodilator Agents - pharmacology; V PHOSPHODIESTERASE; POTENT; ISOFORMS; BOVINE; AORTA; NUCLEOTIDE PHOSPHODIESTERASE; DISCOVERY; CYCLIC-GMP PHOSPHODIESTERASE; Nitro compound; Nitrile; Enzyme; 3',5'-Cyclic-GMP phosphodiesterase; Nitrogen heterocycle; Coronary vasodilator agent; Enzyme inhibitor; Esterases; Phosphoric diester hydrolases; In vitro; Pig; Phthalazine derivatives; Vertebrata; Mammalia; Structure activity relation; Animal; Chlorine Organic compounds; Bicyclic compound; Hydrolases; Aromatic compound; Artiodactyla; Chemical synthesis; Ungulata
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970815r

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 F2 α (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.