uk-81-252 and omapatrilat

Vasopeptidase inhibitors (VPI) are a new promising class of drugs, that simultaneously inhibit Angiotensin - Converting Enzyme (ACE) and an enzyme Neutral Endopeptidase (NEP), that cleaves the natriuretic peptides. These drugs, such as omapatrilat, sampatrilat, fasidotrilat, by combined inhibition of ACE and degradation of natriuretic peptides and in turn by inhibiting the Renin - Angiotensin - Aldosterone system and potentiating the Natriuretic Peptide system and Kinin system should decrease the mortality rate in the group of patients with hypertension being not adequately controlled with ACE inhibitors. Thus, finding the new therapeutic strategy using drugs that act on the hormonal systems other than Renin - Angiotensin - Aldosterone system seems to be crucial. The aim of the study was to compare the molecular aspects of the conventional schemes that are being used in the antihypertension therapy to the new drugs from the vasopeptidase inhibitors group--with focusing on the natriuretic peptide system (NPS)--and, taking these considerations, making clues about therapeutical implications to reveal promising results in antihypertension treatment.

Topics: Alanine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Humans; Hypertension; Mesylates; Protease Inhibitors; Pyridines; Renin-Angiotensin System; Sympathetic Nervous System; Thiazepines; Tyrosine; Vascular Resistance

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

The development of new antihypertensive agents is becoming even more important. We need better blood pressure control and also agents that treat hypertension as a disease of the vascular endothelium. Recently, it has been shown that blocking the renin-angiotensin system with angiotensin converting enzyme (ACE) inhibitors reduces blood pressure and decreases the incidence of vascular disease. Another peptide system, the natriuretic peptide system, has also been shown to be important in blood pressure control and volume homeostasis. Because ACE and neutral endopeptidase, the enzyme responsible for the degradation of the natriuretic peptides, are both zinc metalloproteases, new pharmaceuticals that inhibit both enzymes have been developed. The first of these, omapatrilat, has been shown to be an effective antihypertensive agent and to have great potential for treating congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cardiovascular Diseases; Endothelium, Vascular; Humans; Mesylates; Metalloendopeptidases; Natriuretic Peptide, Brain; Protease Inhibitors; Pyridines; Renin-Angiotensin System; Thiazepines; Tyrosine

Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems and renin-angiotensin-aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependent conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependent degradation of vasodilator atrial natriuretic peptide. Here, we report crystal structures of omapatrilat, sampatrilat, and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75, 2.65, and 2.6 Å, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Crystallography, X-Ray; Drug Design; Mesylates; Neprilysin; Peptidyl-Dipeptidase A; Protein Binding; Protein Structure, Secondary; Pyridines; Thiazepines; Tyrosine