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 synthe sized and tested for their pharmacological profile. These were compare d with the bioisoster ino-4,4a,5,6-tetrahydrobenzo(h)cinnolin-3-(2H)-o ne 1, which we reported to be a potent antihypertensive and antithromb otic agent. Binding studies on phosphodiesterase (PDE) isoenzymes indi cate that the test compounds exhibited a modest affinity towards PDE I II (2c, 3a, b) and PDE V (2b, c). In vivo tests indicated that only 3b displayed antihypertensive properties comparable to the model while a ll the new derivatives exhibited lower hypotensive activity. All compo unds, with the exception of 2b, were more potent than 1 in inhibiting collagen-induced platelet aggregation. Molecular mechanics calculation s were performed on compounds 2 and 3 which were compared with the mod el 1.