Full Papers zyxwvutsrqponmlkjihgfedcbaZWVUTSRQPONMLJIH New Indole and Pyridazinoindole Analogs - Synthesis and Study as Inhibitors of Phosphodiesterases and as Inhibitors of Blood Platelet Aggregation b) Amrinone CH3S Antonio Monge* a \ Maria-Eugenia Navarro a) , Maria Font a) , Esteban Santiago b \ Elena Alberdi and Juan-Jose Martmez-Irujo^ zyxwvutsrqponmlkjihgfedcbaYXWVUTSRQPONMLKJIHGFEDCBA a) Medicinal Chemistry and b) Biochemistry, Centro de Investigation en Farmacobiologia Aplicada (CIFA), Universidad de Navarra, 31080 Pamplona, Spain zyvtsrponlihgedcbaWVKI Key Words: indole, pyridazinoindole, phosphodiesterases, platelet aggregation Summary This paper presents the synthesis of new indole, pyridazino[4,5~&]~ indole, and pyridazino[4,5-a]indole analogs as well as a study of their "in vitro" activity as inhibitors of different phosphodiester- ases isolated from dog cardiac tissue, dog aorta, and bovine plate- lets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro-aggregants, is also included. The selected compounds 8-benzyloxy-3,4-dihydro-1 -(3,4,5~trimethoxy)benzylideneami- nopyridazino[4,5-&]indole 14g, and 8-benzyloxy-4-[(3,5~di~ methyl)pyrazolyl]pyridazmo[4,5-fr]indole 20 present an interest- ing profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8-benzyloxy-3,4-dihydro-1-[4- (methyl)piperazino] acetamidopyridazino [4,5indol-4-one 16c and 8-benzylox|-3,4-dihydro-1-[4-(2-methoxyphenyl)piperaz- ino]acetamidopyridazino[4,5-£]indol-4-one 16f stood out as in- hibitors of platelet aggregation, with a mechanism that could possibly be related to the AA cascade. Introduction Congestive heart failure (CHF) is an illness which affects millions of persons throughout the world, and has a high death rate in spite of the efforts made in the therapeutic field over these past few years The traditional treatment of CHF has been based on the use of cardiac glycosides, diuretics, and vasodilators, either sepa- rately or in combination. However, the pronounced toxic effects and the narrow therapeutic index of the cardiac gly- cosides^ have prompted an extensive search for alternatives to the conventional therapy of this disease, especially for those cases in which conventional long-term treatment is not advisable, having reached a high degree of deterioration or hemodynamic instability, such as in the case of patients with severe CHF requiring a more aggressive therapy, usually intravenous administration of therapeutic a g e n t s ' A l l of this led to the design of new cardiotonic agents such as amri- none milrinone enoximone indolidan and saterinone^ (Figure 1), which in addition, combine the prop- erties of positive inotropes with vasodilator activity in order to achieve maximum improvement in cardiac perform- T9 101 ance L *' 1UJ . Enoximone Indolidan OCH3 Saterinorie Figure 1 The mechanism of action of these compounds could be attributed, at least partly, to the inhibition of phosphodi- estarase isoenzymes which are specific for cyclic adenosine- s',5'-monophospate (cAMP) and consequently to an increase in intracellular cAMP, varying the effectiveness of these compounds considerably for said increase These PDE inhibitors, which initially appeared to hold great therapeutic promise, have scarcely shown clinical benefits in controlled studies. This has interrupted the clinical develop- ment of some of them, as in the case of indolidan others, such as milrinone, are surrounded with controversy concern- ing their efficiency and even the safety in their use in patients zyxwvuts Arch. Pharm. (Weinheim) 328, 689-698 (1995) © VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1995 0365-6233/95/1010-0689 $5.00 + .25/0