6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone - An important chemical moiety for development of cardioactive agents: A review

6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone moiety is a vital structural part of many cardio-active pyridazinone derivatives which are either in clinical use or have been tested in clinical trials. These include imazodan, CI-930, pimobendan, indolidan, levosimendan, SK&F-93741, Y-590, meribendan, NSP-804, NSP-805, bemoradan, senazodan, amipizone, prinoxodan, SKF 95654, siguazodan and KF 15232. This article briefly reviews relevant literature on various reports on the synthesis and use of this moiety for development of cardio-active agents.


INTRODUCTION
Cardiovascular disease is a major public health problem worldwide, even in the United States of America, and it accounts for approximately 30 % of all deaths [1]. Cardiovascular disease has also been considered to be the major cause of death in the Kingdom of Saudi Arabia [2]. Due to increasing prevalence of cardiovascular disease in children, researchers have recommended the establishment of well-equipped hospitals to for the care of children with cardiovascular disease in developing countries as well as in Kingdom of Saudi Arabia [3]. Studies have also revealed that there is a need for more research in the field of cardiovascular disease in developing countries because of the likelihood of prevalence of cardiovascular disease in all age groups in these countries [4,5].
The current review gives an insight on the potential of 6-(4-aminophenyl)-4,5-dihydro-3(2H)pyridazinone moiety for the development of cardio-active agents, and briefly discusses relevant literature related to the synthesis and use of this chemical for the preparation of cardioactive agents. Accordingly, literature references wherein 6-(4-aminophenyl)-4,5-dihydro-3(2H)pyridazinone moiety was not synthesized and/or not used for the preparation of cardio-active agents were excluded.
Thyes et al [29] prepared 6-Aryl-4,5-dihydro-3(2H)-pyridazinones which exhibited aggregation-inhibiting activity on human platelets in vitro and on rat platelets ex vivo, as well as a hypotensive action on rats. The strongest pharmacological effects were found with dihydropyridazinones that have R = chloroalkanoyl substituent, together with a methyl group in the 5-position (3). The hypotensive actions of these compounds were 40 times higher than that of dihydralazine.
These authors further demonstrated that the para-substituted compounds had a strong inhibiting effect on collagen-induced and ADPinduced aggregation of human platelets. It is known that platelet aggregation plays an important role in the pathogenesis of cardiovascular disease [30].
The in vitro human platelet aggregation and the ex vivo rat platelet aggregation-inhibiting activities of 6-aryl-4,5-dihydropyridazinones (4) with R 1 = R 2 = R 4 = Me or H; and R 3 = amine containing, groups were correlated with the van der Waals volume (Vw) of R 3 by Gupta et al [31]. Their results suggested that the size of the substituent on the aryl group plays an important role in the inhibition of platelet aggregation in this series of compounds. Based on the correlating equations obtained, it was further suggested that the inhibition of platelet aggregation most likely involved hydrophobic interaction. A moderate correlation existed between the hypotensive activity of these drugs in rats and Vw, indicating that hypotensive activity also was partly affected by the size of the substituent on the aryl group. Although it was assumed that hydrophobic interactions also played some role in the hypotensive action, it was argued, based on the results, that platelet aggregation inhibition and hypotensive activity involved two different receptor sites. . Most members of this series produced dose-related increases in myocardial contractility that were associated with relative minor increase in heart rate and decrease in systemic arterial blood pressure. Among the synthesized compounds (5), the one with R = H (CI-914) and R = Methyl (CI-930) were more potent than amrinone and milrinone, respectively. It was also postulated that the positive inotropic effect of these compounds was due to the inhibition of cardiac phosphodiesterase fraction III, rather than the stimulation of β-adrenergic receptors. Sircar et al investigated the structure-activity relationships of a series of 4,5-dihydro-6-[4-(1Himidazol-1-yl)phenyl]-3-(2H)-pyridazinones (7) with R = H, Me, CH 2 Ph, CH 2 CH 2 OH, CH 2 CH 2 OAc; R 1 = H, Me, NH 2 , CONH 2 ; and R 2 = H, Me, Et; R 3 = H, Me, SH, SMe, SOMe, Et, for their in vivo inhibition of different forms of cyclic nucleotide phosphodiesterase (PDE) isolated from guinea pig ventricular muscle [34]. With few exceptions, these 4,5-dihydropyridazinones were potent inhibitors of cardiac type III phosphodiesterase. The most selective PDE III inhibitor was CI-930 (R = R 1 = R 3 = H, R 2 = Me) with an ED 50 of 0.6 µM.
Slater et al [35] reported the design and synthesis of a series of combined vasodilator-βadrenoceptor antagonists based on 6arylpyridazinones, and evaluated them as vasodilator-β-adrenoceptor antagonists and potential antihypertensive agents. Many of the synthesized compounds showed high level of intrinsic sympathomimetic activities (ISA) and relatively short durations of action. Di-substitution in the 2,3-positions or in the 4-position of the aryloxy ring produced compounds with low ISA levels and, in some cases, improved duration of action. The 5-methylpyridazinone derivatives displayed more antihypertensive activity than their 5-H homologs. The compound, SK&F 95018, was selected for further development.
Alfred et al [37] have reported 4,5-dihydro-6-(1Hindol-5-yl)-pyridazin-3(2H)-ones and related compounds with positive inotropic activities. Most of these compounds produced increases in myocardial contractility with little effects on heart rate and blood pressure. The cardiotonic effect of compound (10) was at least 2-fold higher than that of pimobendan following oral administration.
It has been suggested that, for optimal cardiotonic activity within this class of indole derivatives, a heterocyclic aromatic ring in position 2, a hydrogen or a Me group in position 3 and a dihydropyridazinone ring system in position 5 of the indole are necessary.
ones have been synthesized and their PDE III inhibitory, inotropic and vasodilator potencies compared with those of their normethyl and their bicyclic 4,5-dihydro-6-phenylpyridazinone analogues by Bakewell et al [38]. The study revealed that the structure-activity relationships of the tricyclic pyridazinones differ from those of bicyclic pyridazinones mainly in respect of the effect produced by introducing a methyl group in the pyridazinone ring. Introduction of a 5-methyl group has been widely reported to lead to compounds of significantly greater potencies in the 4,5-dihydro-6-phenylpyridazin-3(2H)-ones. On the other hand, the tricyclic 4amethylpyridazinones showed similar levels of inotropic, vasodilator and PDE III inhibitory potencies to their normethyl analogues. In this series of compounds, the tricyclic 4amethylpyridazinones (11) with R = cyano, CONH2, NH2, NHAc, or OMe, and n = 1,2, …., showed good inotropic, vasodilator and PDE III inhibitory potencies. The synthesis and platelet aggregation-inhibitory activities of 6-(4-substituted acylamidophenyl)-4,5-dihydro-3(2H)-pyridazinones and 6-(4substituted acylaminophenyl)-4,5-dihydro-3(2H)pyridazonones have been described by Liu et al [43,44]. Preliminary pharmacological tests revealed that all the synthesized compounds inhibited appreciable ADP-induced platelet aggregation activities in rabbits. Liu et al [45] have further reported synthesis of 6-(4substituted acylaminophenyl)-4,5-dihydro-3(2H)pyridazinones and their inhibitory actions on platelet aggregation. These compounds were synthesized based on structure-activity relationships of anti-platelet aggregation of dihydropyridazinones.

CONCLUSION
Cardiovascular disease has become the leading cause of death worldwide and remains the foremost cause of preventable death globally. The need for more research in the field of cardiovascular disease in developing countries is underscored by the prevalence of cardiovascular disease in all age group of patients in these countries. 6-(4-Aminophenyl)-4,5-dihydro-3(2H)pyridazinone is an important chemical moiety that is useful for the development of cardio-active agents. The potential of its derivatives as cardioactive agents is evident from the literature as reviewed in this article. It is our belief that the exploitation of 6-(4-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone derivatives can produce more potent cardio-active agents for clinical use in the treatment of cardiovascular disease.