Inotropic agents in development

Abstract

The aim of this review is to describe the mechanisms of action and the clinical potential of new inotropic agents in the treatment of congestive heart failure (CHF). Digitalis-like activity has been found in certain alkaloids of Erythrophleum lasianthum, which inhibit the sodium-potassium adenosine-triphosphatase and induce inotropic effects in vitro. Inhibition of phosphodiesterase III (PDE III) and increased intracellular levels of cyclic adenosine monophosphate have been established as the mechanism for the inotropic, lusitropic and vasodilating effects of the bipyridine derivatives, amrinone and milrinone, the imidazolone analogues, enoximone and piroximone, the pyridazinone analogue, imazodan, and the recently synthesised RGW-2938 (Laboratories Rorer International), NSP-804 and NSP-805 (Nippon Soda). Agents that have been shown to inhibit PDE III and to increase the calcium sensitivity of contractile proteins include the benzimidazole derivatives, pimobendan and adibendan, the bipyridine compound, sulmazole, the quinoline derivatives, nanterinone and vesnarinone, the benzothiophene derivative, ORG30029 and the thiadiazinone derivatives, EMD 53998 and ORG 30029. New approaches to the treatment of CHF are offered by agents that combine the inhibition of PDE III with beta-adrenoceptor blockade (compound GI 104313), or the activation of calcium channels with alpha₁-adrenoceptor blockade (compound XB513). The Na⁺ channel modulators, DPI 201–106 (Sandoz) and BDF 9148 (Beiersdorf), act by preventing the inactivation of Na⁺ channels. The recently synthesised analogues of milrinone, SF28 and SF40, have been shown to induce inotropic effects mainly through the antagonism of endogenous adenosine at A₁ inhibitory receptors.