3,4-Dihydroquinolin-2(1H)-ones as combined inhibitors of thromboxane A2 synthase and cAMP phosphodiesterase.
A series of 1H-imidazol-1-yl- and 3-pyridyl-substituted 3,4-dihydroquinolin-2(1H)-ones was designed and synthesized as combined inhibitors of thromboxane (TXA2) synthase and cAMP phosphodiesterase (PDE) in human blood platelets. A number of structures, e.g. 4b, 7a, 7e, 13a, and 21-25, were superior to dazoxiben 26 as inhibitors of TXA2 synthase in in vitro ADP-induced aggregation experiments with human blood platelets. The TXA2 synthase inhibitory activity was confirmed by measurement of the prostanoid metabolites derived from 14C-labeled arachidonic acid. Three compounds (7a, 7e, and 25) demonstrated in vitro inhibition of human platelet cAMP PDE at micromolar concentrations in conjunction with their TXA2 synthase inhibitory activity. Synergistic enhancement of antiaggregatory and antithrombotic actions was expected when simultaneous stimulation of adenylate cyclase (through increased PGI2 production) and inhibition of platelet cAMP PDE were possible from the same compound. Ex vivo and in vivo experiments were conducted in rats and mice, respectively, to evaluate the effects of compounds 7e and 23 on platelet aggregation and thrombotic events within these animals. Compound 7e, which has a comparable level of TXA2 synthase (IC50 1.2 microM) and human platelet cAMP PDE (IC50 6.4 microM) inhibitory activities, was found to be orally bioavailable with a long duration of action and offered effective protection against mortality in a collagen-epinephrine-induced pulmonary thromboembolism model in mice. Significant blood pressure and heart rate effects were observed for several compounds, e.g. 7e, 9e, 13a, 13d, 18, 20, 21, and 23, when dosed orally in conscious spontaneously hypertensive rats.
Martinez
G R
GR
Institute of Organic Chemistry, Syntex Research, Palo Alto, California 94304.
Walker
K A
KA
Hirschfeld
D R
DR
Bruno
J J
JJ
Yang
D S
DS
Maloney
P J
PJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000201:enzymology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008861:Microsomes / Q000201:enzymology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D013552:Swine; D013923:Thromboembolism / Q000188:drug therapy; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D015363:Quinolones; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D000244:Adenosine Diphosphate; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D013930:Thromboxane-A Synthase