Description
Amrinone is a positive inotropic agent useful in the management of severe congestive
heart failure. It is effective even in unresponsive, fully digitalized patients.
Chemical Properties
Crystalline Solid
Originator
Sterling-Winthrop (USA)
Uses
A selective cAMP phosphodiesterase (PDE-3) inhibitor with positive inotropic and vasodilatory activity. Cardiotonic
Uses
Amrinone is used for short-term treatment of cardiac insufficiency that does not respond to treatment of other drugs.
Uses
analgesic, antipyretic, antiinflammatory
Definition
ChEBI: Amrinone is a 3,4'-bipyridine substituted at positions 5 and 6 by an amino group and a keto function respectively. A pyridine phosphodiesterase 3 inhibitor, it is a drug that may improve the prognosis in patients with congestive heart failure. It has a role as an EC 3.1.4.* (phosphoric diester hydrolase) inhibitor.
Manufacturing Process
A mixture containing 10g of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 200 ml
of dimethylformamide and 1.5 g of 10% palladium-on-charcoal was
hydrogenated under pressure (50 psi) at room temperature until the uptake of
hydrogen ceased (about 30 minutes). The reaction mixture was filtered
through infusorial earth and the filtrate was heated in vacuum to remove the
solvent. The residual material was crystallized from dimethylformamide,
washed successively with ethanol and ether, and dried in a vacuum oven at
80°C for 8 hours to yield 6 g of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone,
melting point 294° to 297°C with decomposition.
Brand name
Inocor
(Sterling Winthrop).
Therapeutic Function
Cardiotonic
General Description
During normal heart function, cAMP performsimportant roles in regulating intracellular calcium levels.That is, certain calcium channels and storage sites forcalcium must be activated by cAMP-dependant protein kinases.Because cAMP plays an indirect role in the contractilityprocess, agents that inhibit its degradation will providemore calcium for cardiac contraction. One phosphodiesteraseenzyme that is involved in the hydrolysis of myocardiumcAMP is F-III. Amrinone, 5-amino (3,4 -dipyridin)-6 1 (H)-one (Inocor), possesses positive isotropic effects as aresult of its ability to inhibit this phosphodiesterase. In 1999,the USP Nomenclature Committee and the United StatesAdopted Names (USAN) Council approved changing thenonproprietary name and the current official monograph titleof amrinone to inamrinone. This change in nomenclature wasa result of amrinone being confused with amiodarone becauseof the similarity of the names. This was reported to cause confusionbetween the products that led to medication errors,some of which resulted in serious injury or death.
Safety Profile
Poison by ingestion andintravenous routes. Human systemic effects by ingestion:cardiac arrhythmias, liver function, thrombocytopenia. Anexperimental teratogen. Other experimental reproductiveeffects. When heated to decomposition it emits toxicfumes o
Synthesis
Amrinone, 3-amino-5-(4-piridinyl)-2(1H)-pyridinone (17.2.4), can be synthesized
from piridine-4-acetic acid, the reaction of which with a mixture of diemthylformamide?a
phosphorous oxychloride gives 2-(4-piridyl)-3-dimethylaminoacrolein (17.2.1).
Reacting this with cyanoacetamide gives 3-cyano-5-(4-piridyl)-2(1H)-pyidinone (17.2.2).
Hydrolysis of the cyano group of this product gives 3-carbamyl-5-(4-piridyl)-2(1H)-pyidinone
(17.2.3). A Hofmann rearrangement of this product (using bromine in sodium
hydroxide) gives amrinone (17.2.4).
An alternative method for the synthesis of amrinone from 3-cyano-5-(4-piridyl)-2(1H)-
pyridinone (17.2.2) is based on it?ˉs acidic hydrolysis to the corresponding acid, 3-carboxy-
5-(4-piridyl)-2(1H)-pyridinone (17.2.5), nitration of which with nitrous acid in the presence
of sulfuric acid forms 3-nitro-5-(4-piridyl)-2(1H)-pyridinone (17.2.6). Reducing the nitro
group of this product with hydrogen gives the desired amrinone (17.2.4).
