Synthesis and cyclic AMP phosphodiesterase 4 isoenzyme inhibitory activity of heterocycle condensed purines.
To reverse the adverse reactions of alkylxanthines and to develop novel inhibitors of cyclic AMP phosphodiesterase 4 (PDE4), a series of heterocycle [a]-, [b]-, [c,d]-, and [i]-condensed purines were designed and synthesized. Although all compounds did not display PDE1 and PDE3 inhibitory activities, several heterocycle [i]-condensed purines strongly inhibited PDE4. Especially, dl-3,4-dipropyl-8-methyl-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one (dl-7c) exhibited comparable PDE4 inhibitory activity (IC(50)=1.9 microM) to rolipram and denbufylline (DBF).
Suzuki
Hirokazu
H
Department of Synthetic Chemistry, Hokuriku University, Kanazawa, Japan. h-suzuki@hokuriku-u.ac.jp
Yamamoto
Manabu
M
Shimura
Susumu
S
Miyamoto
Ken-ichi
K
Yamamoto
Kenji
K
Sawanishi
Hiroyuki
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D009682:Magnetic Resonance Spectroscopy; D043264:Phosphodiesterase I; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology*
D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011687:Purines; D010727:Phosphoric Diester Hydrolases; D043264:Phosphodiesterase I; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4