An Orally Effective Peripheral Dopamine Prodrug: Docarpamine (TA‐870)

Abstract

Intravenous infusion of dopamine (DA) has been widely used in patients with acute heart failure, shock, and acute renal failure (4-7,18,19). However, since DA is rapidly inactivated by sulfotransferase, monoamine oxidase (MAO), and catechol-0-methyltransferase (COMT) in the intestinal wall and liver, plasma free DA levels scarcely rise to therapeutically effective concentrations when this drug is administered orally (20,22,35,36).Docarpamine is a derivative of DA that was designed as an orally active prodrug (36). It effectively elevates the plasma free DA level by reducing first-pass metabolism when administered by the enteric route (43). Oral docarpamine shows renal vasodilatory and natriuretic effects by activating renal DA, receptors, and a positive inotropic effect by activating cardiac PI-receptors via free DA (26,28-30,36). Docarpamine and its metabolites do not cross the blood-brain barrier, and show no effect on the central nervous system (CNS) even at high doses (3). It has a weaker emetic effect than levodopa (25). Clinical trials show that docarpamine can be used as a practical alternative to DA infusion (8,15,17,21,37). Docarpamine is an orally effective peripheral DA prodrug capable of improving renal and cardiac function by oral administration. CHEMISTRYDocarpamine was designed to protect the catechol and amino moieties of DA with ethoxycarbonyl and acetylmethionyl groups, respectively. The chemical name of docarpamine is N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (Fig. 1). Its molecular weight is 470.54, the empiric formula is C,,H&O,S, and its melting point is 105-108°C. Docarpamine is available as a white crystalline powder. It is slightly soluble in water, and readily soluble in ethanol.

Prodrugs for Amines

“…A well-known example of the former is the exploitation of renal γ-glutamyl transpeptidase as a vector for amino drug release from γ-glutamic acid conjugates [ 10 ]. Dopamine has been a candidate for this and numerous other prodrug approaches because it is inactivated by sulfotransferase, MAO and COMT in the intestinal wall and liver [ 11 ] following oral administration [ 12 ]. The dopamine double prodrug, γ-glutamyl-L-dopa (gludopa), achieves kidney dopamine levels about five-fold higher than those obtained with an equimolar quantity of the single prodrug L -dopa [ 13 ].…”

“…Docarpamine is well absorbed from the oral route, has weak intrinsic vasodilatory effects [ 17 ], has no effect in the CNS even at high doses [ 11 ], and is easily converted to dopamine in vivo [ 15 ]. Non-peptide N -acyl derivatives of dopamine have also been evaluated [ 18 ].…”