Selective Inhibitors of Cyclic AMP-Specific Phosphodiesterase:  Heterocycle-Condensed Purines

• Published in: Journal of medicinal chemistry Vol. 40; no. 20; pp. 3248 - 3253
• Main Authors: Sawanishi, Hiroyuki, Suzuki, Hirokazu, Yamamoto, Shinya, Waki, Yoshihiro, Kasugai, Shohei, Ohya, Keiichi, Suzuki, Nagao, Miyamoto, Ken-ichi, Takagi, Kenzo
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 26.09.1997
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Administration, Oral; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Cyclic Nucleotide Phosphodiesterases, Type 4; Depression, Chemical; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Heart - drug effects; Hydrolases; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Male; Models, Chemical; Muscle Relaxation - drug effects; Myocardium - enzymology; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - pharmacology; Purines - chemical synthesis; Purines - pharmacology; Shrews; Trachea - enzymology; Heart; Angular nitrogen heterocycle; Central nervous system; Esterases; Phosphoric diester hydrolases; A2 Adenosine receptor; Structure activity relation; Antispasmodic agent; Vomiting; Antagonist; Chemical synthesis; Insectivora; 3',5'-Cyclic-nucleotide phosphodiesterase; Enzyme; Oral administration; Enzyme inhibitor; Suncus murinus; Tricyclic compound; In vitro; Heart rate; In vivo; Vertebrata; Mammalia; Animal; Hydrolases; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970089s

To reverse the adverse reactions of alkylxanthines and to develop novel inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), a series of heterocycle-condensed purines were designed and synthesized. Some of these new compounds had similar or more potent and selective inhibitory activity against PDE IV than known PDE IV inhibitors. The tracheal-relaxant activity of these compounds was closely correlated with their PDE IV-inhibitory activity. Moreover, these purine analogues did not have any positive-chronotropic action or adenosine-antagonistic action on isolated heart preparations, which are the particular adverse reactions of alkylxanthines. Among them, 3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-i]purin-5-one (1c), which was the most selective and potent PDE IV inhibitor, did not cause emesis in Suncus murinus at a dosage range of 10−100 mg/kg (po), while an imidazole analogue of 1c (4c) and known PDE IV inhibitors such as rolipram and denbufylline caused emesis even at 10 or 30 mg/kg.