1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-ones--inhibitors of Blood Platelet cAMP Phosphodiesterase and Induced Aggregation

J Med Chem. 1991 Sep;34(9):2906-16. doi: 10.1021/jm00113a033.

Abstract

A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives was synthesized and evaluated as inhibitors of cAMP hydrolysis by a crude human platelet phosphodiesterase preparation and as inhibitors of ADP- and collagen-induced aggregation of rabbit blood platelets. The parent structure 7a, demonstrated potent inhibitory activity that was enhanced by the introduction of alkyl, alkoxy, or halogen substituents at the 5-, 6-, 7-, and 8-positions. Methylation at N-1 or N-3 produced weaker inhibitors of cAMP PDE and platelet aggregation. 1,3,9,9a-Tetrahydro-2H-imidazo[4,5-b]quinolin-2-ones (6) were found to be equipotent with their fully oxidized congeners (7). On the basis of platelet inhibitory properties in vitro, efficacy at preventing thrombus formation in animal models of thrombosis, and a favorable hemodynamic profile, 1,3-dihydro-7,8-dimethyl-2H- imidazo[4,5-b]quinolin-2-one (7o, BMY 20844) was selected for advancement into toxicological evaluation and clinical trial. An efficient synthesis of 7o is described.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Adenosine Diphosphate / antagonists & inhibitors
  • Animals
  • Blood Platelets / drug effects
  • Blood Platelets / enzymology*
  • Drug Design
  • Imidazoles / pharmacology*
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / pharmacology*
  • Quinolones / pharmacology*
  • Rabbits
  • Rats

Substances

  • Imidazoles
  • Platelet Aggregation Inhibitors
  • Quinolones
  • Adenosine Diphosphate
  • 3',5'-Cyclic-AMP Phosphodiesterases