Amrinone, cardiotonic

The narrow therapeutic range of digitalis related cardiotonic agents has resulted in an extensive effort to identify compounds in other structural classes which will improve cardiac function. The discovery of the heterocyclic cardiotonic drug, amrinone, led to research on other heterocyclic compounds for that indication. The imidazopyridine, isomazole (57), is representa-... 

Fig. 1 Heterocycles bearing a 2-pyridone moiety with wide range of medicinal applications. Amrinone WIN 40680 1 is a cardiotonic agent for the treatment of heart failure. ZAR-NESTRA 2 is a selective farnesyl protein inhibitor and NP048 3 is a pilicide with novel antibacterial properties. The 2-pyridones 4, 5 and 6 are schematic representations of the three categories of 2-pyridones that wiU be covered in this chapter i.e., substituted 2-pyridones 4, 2-quinolones 5 and other ring-fused 2-pyridones 6...

The discovery of the positive inotropic and systemic vasodilator activities of bipyridine-derived compounds, like amrinone (7) and milrinone (8), has markedly stimulated research aimed at the development of structurally related non-steroidal, non-catecholamine cardiotonics. In this context, a wide variety of pyridazinone derivatives have been prepared and investigated in search for novel agents useful for the chronic management of congestive heart failure. 

It has been claimed that cardiotonic activity is retained upon replacement of the pyridone moiety in the amrinone molecule by a 3(2 /)-pyridazinone system (9) [7]. Moreover, the patent literature covers various cardiotonic 6-(pyridyl)-3(2//)-pyridazinones and 4,5-dihydro congeners as exemplified by (10), which have been developed in the United States [8-11], Also 3-amino-... 

From this series, compound MCI-154 (CAS 98326-33-1) (30) has been investigated in detail [95,96]. In vivo studies (anaesthetized dogs) revealed that doses of 0.3-100 tg/kg (i.v. administration) of MCI-154 produce dose-dependent increases in dF/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance. The positive inotropic effect of (30) has been found to be superior to that exhibited by amrinone and milrinone [97,98]. It has been stated that MCI-154 exerts its activity probably by increasing the calcium-ion sensitivity of the contractile protein system of the cardiac skinned fibres [99,100]. A recent investigation suggests that inhibition of phosphodiesterase III is an important component of its cardiotonic activity [101]. 

Bipyridine resembles nicotine in its pharmacological properties but is not as active. The 3,4 -bipyridine derivative 113 known as amrinone and its relatives are of interest as cardiotonic agents. 4,4 -Bipyridine has been tested as an insecticide, but it is not of practical value.It is used in the study of the electrochemistry of cytochrome c and acts as a polymerization catalyst or hardening agent for various resins. l-Hexyl-4,4 -bipyridinium salts are especially effective as electron carriers in photochemical hydrogen producing systems. l,l -Dimethyl-4,4 -bipyridinium (92 R = R = CHj) and l,l -dibenzyl-4,4 -bipyridinium... 

The role of the pyridone ring as a pharmacophore in cardiotonic agents such as amrinone (25-6) has been noted earlier very analogous activity is obtained with compounds in which the heterocylic ring is replaced by a pyridazinone. The synthesis of the first of these agents, pimobendan (35-6), starts with the acylation of the amino group in nitro-aniline (35-2) with anisoyl chloride (35-1) to give amide (35-3). 

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