TZC-5665 (Oberadilol) is a pyridazinone derivative with vasodilatory and beta-adrenergic blocking activities and type III phosphodiesterase inhibitory action

Bucindolol is a third-generation, non-selective β-adrenergic receptor blocker, that acts on both β-1 and β-2 receptors. Bucindolol’s additional α-1 antagonistic activity contributes to its mild vasodilator effect. It was rejected by the FDA for the heart failure, because of the unreviewed submissions deal with comparative effectiveness, clinical pharmacology, some aspects of pharmacogenetic data, and toxicology/metabolism. In addition, bucindolol is in the phase II of clinical trial for the treatment of atrial fibrillation.

Xamoterol (ICI 118,587) is a partial agonist of beta1-adrenoceptors. Xamoterol acts on the cardiac beta 1-adrenergic receptor, modifies the response of the heart to variations in sympathetic activity. At rest, it produces modest improvements in cardiac contractility, relaxation, and filling without increase in myocardial oxygen demand. The improvements are maintained during exercise although the attendant tachycardia is attenuated. The beneficial effects of xamoterol on both systolic and diastolic function suggested that it would be effective in patients with mild-to-moderate heart failure, and this was demonstrated in small placebo-controlled studies where effort tolerance and symptoms were improved. Xamoterol produced improvements in exercise capacity, clinical signs, symptoms and quality of life with a low incidence of adverse experiences. Xamoterol is effective as monotherapy in heart failure.

Sitaxentan (TBC11251, trade name Thelin) is a potent and selective Endothelin A receptor antagonist. Sitaxentan was under development by Encysive Pharmaceuticals (now Pfizer) for use in the treatment of pulmonary hypertension, congestive heart failure and asthma. It was launched in the major markets of the European Union (EU) under name Thelin for the treatment of pulmonary arterial hypertension. In December 2010, Pfizer discontinued clinical trials of sitaxentan worldwide and initiated voluntary product withdrawal from markets where it is approved due to life-threatening idiosyncratic risk of liver injury.

Dopexamine hydrochloride is a synthetic catecholamine, structurally related to dopamine, with marked intrinsic agonist activity at beta 2-adrenoceptors, lesser agonist activity at dopamine DA1- and DA2-receptors and beta 1-adrenoceptors, and an inhibitory action on the neuronal catecholamine uptake mechanism. The drug is administered by intravenous infusion, and is characterized by a rapid onset and short duration of action. Dopexamine is being tested as a treatment for heart failure and sepsis.

Istaroxime is a novel intravenous agent with luso-inotropic properties that acts by inhibition of Na( )/K( ) adenosine triphosphatase and stimulation of sarco/ endoplasmic reticulum calcium ATPase isoform 2. It is significantly decreased left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, heart rate and increased systolic blood pressure and cardiac index with no change in neurohormones, renal function or troponin I. Istaroxime has successfully concluded phase II clinical trials in cardiac failure patients. Istaroxime induced apoptosis, affected the key proliferative and apoptotic mediators c-Myc and caspase-3 and modified actin cytoskeleton dynamics and RhoA activity in prostate cancer cells – this provides novel insights into the anti-cancer properties of istaroxime further supporting the development of this agent as a novel anti-cancer drug candidate.