Synthesis and pharmacological evaluation of thienocinnolin- 3(2H)ones, bioisosters of antihypertensive and antithrombotic benzo(h)cinnolinones

A number of thienocinnolin-3-(2H)-ones (2b, c; 3a, b) have been synthesized and tested for their pharmacological profile. These were compared with the bioisoster 8-acetylamino-4,4a,5,6-tetrahydrobenzo(h)cinnolin-3-(2H)-one 1, which we reported to be a potent antihypertensive and antithrombotic agent. Binding studies on phosphodiesterase (PDE) isoenzymes indicate that the test compounds exhibited a modest affinity towards PDE III (2c, 3a, b) and PDE V (2b, c). In vivo tests indicated that only 3b displayed antihypertensive properties comparable to the model while all the new derivatives exhibited lower hypotensive activity. All compounds, with the exception of 2b, were more potent than 1 in inhibiting collagen-induced platelet aggregation. Molecular mechanics calculations were performed on compounds 2 and 3 which were compared with the model 1.