Selective inhibitors of cyclic AMP-specific phosphodiesterase: heterocycle-condensed purines.
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.
Sawanishi
H
H
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Suzuki
H
H
Yamamoto
S
S
Waki
Y
Y
Kasugai
S
S
Ohya
K
K
Suzuki
N
N
Miyamoto
K
K
Takagi
K
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003864:Depression, Chemical; D006321:Heart / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008956:Models, Chemical; D009126:Muscle Relaxation / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*; D012788:Shrews; D014132:Trachea / Q000201:enzymology
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011687:Purines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4