Amrinone

Chemical Name 3-Amino-5- 4-pyridinyl)-2 1 H)-pyridinone Common Name — 

---

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

Four tested compounds at 10 ° M concentration increased the contraction of guinea pig heart more effectively than amrinone (86JAP(K)1). 

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...

CJH4N2O 107-91-5) see Alloputinol Amrinone Ethionamide Milrinone Nevirapine Olprinone hydrochloride Protionamide cyanoacetic acid... 

C3H7NO 68-12-2) see Acrivastine Amlexanox Amrinone Etretinate Fluvastatin sodium Gitaloxin Glymidine Isradipine Lonazolac Nomegestrol acetate Sulfaperin... 

Abciximab, aminophylline, amiodarone, amrinone, aspirin, carbamazepine, chlorpromazine, danazol, diltiazem, eptifi-batide, heparin, histamine2-receptor antagonists, low molecular weight heparins, methyldopa, milrinone, procainamide, quinidine, quinine, NSAIDs, thiazide diuretics, ticlopidine, tirofiban, and valproic acid... 

Milrinone is a bipyridine derivative that inhibits phosphodiesterase 111 and produces positive inotropic and arterial and venous vasodilating effects hence, milrinone has been referred to as an inodilator. It has supplanted use of amrinone, which has a higher rate of thrombocytopenia. 

Meisheri K D, Palmer RF, van Breemen C 1980 The effects of amrinone on contractility, Ca2+ uptake and cAMP in smooth muscle. Eur J Pharmacol 61 159—165 Miriel VA, Mauban JR, Blaustein MO, Wier WG 1999 Local and cellular Ca2+ transients in smooth muscle of pressurized rat resistance arteries during myogenic and agonist stimulation. J Physiol 518 815-824... 

PDE3 cGMP-inhibited PDE cAMP cGMP cGMP, milrinone, amrinone, anagrelide, cilostazol, lixazinone, NSP-513... 

Amphoteric water-soluble polymers, 20 475 Ampicillin, registered for use in aquaculture in Japan, 3 221t AmpliChip CYP450 Test, 16 392 Amplifiers, optical, 11 145-146 Amrinone, 5 186... 

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]. 

The methylxanthine theophylline (p. 326), the phosphodiesterase inhibitor amrinone (p. 132), prostacyclins (p. 197), and nicotinic acid derivatives (p. 156) also possess vasodilating activity. 

Parasympathomimetics and sym-pathomimetics act at membrane receptors for visceromotor neurotransmitters. The plasmalemma also harbors the sites of action of cardiac glycosides (the Na/K-ATPases, p. 130), of Ca + antagonists (Ca2+ channels, p. 122), and of agents that block Na channels (local anesthetics p. 134, p. 204). An intracellular site is the target for phosphodiesterase inhibitors (e.g., amrinone, p. 132). 

---