uk-81-252 and Heart-Failure

Vasopeptidase inhibitors are a group of agents capable of inhibiting neutral endopeptidase and angiotensin-converting enzymes, which leads to potentiation of natriuretic peptide actions and suppression of the renin-angiotensin-aldosterone system. With this distinctively characteristic mechanism, these agents have emerged as a new drug class for management of hypertension and heart failure. Several vasopeptidase inhibitors are under clinical investigation. Omapatrilat is the most studied agent in this class. Clinical studies of omapatrilat in hypertension have consistently shown the agent's effectiveness in a variety of patient populations. In patients with heart failure, omapatrilat significantly improved neurohormonal and hemodynamic status. Long-term effects of omapatrilat in patients with heart failure recently were compared with those of conventional therapy in a large phase II trial. Results of the study appear promising. Large clinical trials are ongoing, and additional information regarding safety and efficacy from these studies may help define the place in therapy for this agent.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Heart Failure; Humans; Hypertension; Lisinopril; Mesylates; Natriuretic Peptide, Brain; Neprilysin; Pyridines; Randomized Controlled Trials as Topic; Thiazepines; Tyrosine

Sampatrilat is a novel vasopeptidase inhibitor that may offer a greater benefit than traditional angiotensin-converting enzyme (ACE) inhibitors in the treatment of chronic heart failure (CHF). The present study was undertaken to determine whether sampatrilat improves hemodynamic function and cardiac remodeling through a direct action on the failing heart in rats with CHF following left coronary artery ligation (CAL). Sampatrilat (30 mg/kg a day) was administered orally to the animals from the 1st to 6th week after the operation. Sampatrilat reduced the mortality of the rats with CAL (20 versus 57% for untreated rats). Treatment with sampatrilat for 5 weeks suppressed tissue ACE and neutral endopeptidase (NEP) activities. Sampatrilat did not affect the arterial blood pressure, whereas it attenuated the CAL-induced increases in the left ventricular end-diastolic pressure, heart weight, and collagen content of the viable left ventricle. To assess the direct effects of sampatrilat on collagen synthesis, we measured the incorporation of [(3)H]proline into cultured cardiac fibroblasts. Sampatrilat at concentrations that inhibited NEP activity in vitro augmented the atrial natriuretic peptide-induced decrease in [(3)H]proline incorporation by the cells. In addition, sampatrilat prevented the angiotensin I-induced increase in [(3)H]proline incorporation, whereas captopril did not. The results suggest that long-term treatment with sampatrilat regresses cardiac remodeling in rats with CAL, which is associated with improvement of hemodynamic function. The mechanism by which sampatrilat improved cardiac remodeling may be attributable to the direct inhibition of cardiac fibrosis, possibly acting through the cardiac natriuretic peptide system.

Topics: Animals; Chronic Disease; Collagen; Disease Models, Animal; DNA; Enzyme Inhibitors; Fibroblasts; Heart Failure; Hemodynamics; Ligation; Male; Mesylates; Myocardial Infarction; Myocardium; Neprilysin; Organ Size; Peptide Hydrolases; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Tyrosine; Ventricular Remodeling

Sampatrilat is a dual inhibitor of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE), which is under development by Pfizer and Shire (previously Roberts Pharmaceutical) for the potential treatment of hypertension. As of 1995, Pfizer had taken the compound into phase II clinical trials [179233]. In April 1997, Roberts Pharmaceutical, through its wholly owned subsidiary Roberts Laboratories Inc, received an exclusive license from Pfizer to develop and market sampatrilat for the treatment of essential hypertension and congestive heart failure. The agreement provided for transfer of data and the awarding of patent rights to Roberts [240809]. Although in June 2000, Shire confirmed it had discontinued all development of this drug [372652], by December 2000 it had recommenced studies with a reformulation of sampatrilat that achieved a 4-fold increase in oral bioavailability. A clinical trial with the new formulation was to be initiated in 2001, with results expected during the second quarter of 2001. The company also revealed that it was seeking a licensing partner at this time [394238]. In November 2001, Shire confirmed that while the project was undergoing further development with a view to outlicensing, it was unlikely to take this project into phase II alone [429562].

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Contraindications; Endopeptidases; Heart Failure; Humans; Hypertension; Mesylates; Protease Inhibitors; Structure-Activity Relationship; Tyrosine