uk-81-252 and Hypertension

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

Our objective was to evaluate the safety and antihypertensive efficacy of sampatrilat, a novel dual inhibitor of both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in subjects poorly responsive to ACE inhibitor monotherapy. The ability of sampatrilat (50 to 100 mg daily) (n = 28) to lower blood pressure was compared with that of the ACE inhibitor lisinopril (10 to 20 mg daily) (n = 30) using a double-blind, randomized, parallel group study design over a 56-day treatment period in black hypertensives. Changes in systolic (SBP) and diastolic (DBP) blood pressure were determined using repeated ambulatory blood pressure (ABP) monitoring. Both sampatrilat and lisinopril decreased plasma ACE concentrations after 28 and 56 days. The decrease in plasma ACE concentrations (U/L) was greater after lisinopril (-9.33 +/- 0.52) as compared with sampatrilat (-6.31 +/- 0.70) (P = .0001) therapy. Lisinopril, but not sampatrilat, increased plasma renin activity. Lisinopril produced a transient decrease in mean 24-h ABP (mm Hg) at 28 days (SBP = -9.0 +/- 2.3, DBP = -5.7 +/- 1.3; P < .01), which returned to pretreatment values by 56 days of therapy. Alternatively, sampatrilat produced a sustained decrease in mean ABP over the 56-day treatment period (day 28: SBP = -7.3 +/- 1.8, DBP = -5.2 +/- 1.2; P < .01: day 56: SBP = -7.8 +/- 1.5; DBP = -5.2 +/- 0.95; P < 0.01) with a greater treatment effect on DBP than that of lisinopril at day 56 (P = .05). Treatment-emergent adverse events were noted to be similar between both treatment groups. We conclude that the antihypertensive actions of ACE/NEP inhibitor monotherapy in black subjects offers a novel therapeutic approach to patients otherwise resistant to the sustained antihypertensive actions of ACE inhibitor monotherapy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Black People; Blood Pressure; Double-Blind Method; Enzyme Inhibitors; Female; Heart Rate; Hormones; Humans; Hypertension; Lisinopril; Male; Mesylates; Middle Aged; Neprilysin; Tyrosine

The antihypertensive response to angiotensin-converting enzyme (ACE) inhibitors may be attenuated by a compensatory decrease in atrial natriuretic factor production. If so, inhibition of atrial natriuretic factor breakdown by neutral endopeptidase (NEP) may enhance the antihypertensive effects of ACE inhibition. We compared effects of the combined ACE-NEP inhibitor sampatrilat, lisinopril, and placebo on blood pressure, plasma ACE, and renin activity and urinary cyclic guanosine monophosphate (cGMP) of patients with hypertension.. After a 4-week placebo run-in period, 124 patients with a mean blood pressure of 162/102 mm Hg were randomized in a double-blind parallel-group design to 1 of 5 treatments, given once daily for 10 days: 50 mg, 100 mg, or 200 mg sampatrilat; 20 mg lisinopril; or placebo. The first dose of sampatrilat did not lower clinic or ambulatory blood pressure. Lisinopril had an immediate antihypertensive effect that differed significantly from all doses of sampatrilat. After 10 days of treatment, sampatrilat lowered clinic and ambulatory blood pressure significantly at all doses, with a trend toward a dose response for systolic ambulatory blood pressure. Sampatrilat inhibited plasma ACE in a dose-dependent fashion but significantly less so than lisinopril on days 1 and 10 of treatment. Lisinopril but not sampatrilat significantly increased plasma renin activity, whereas sampatrilat but not lisinopril significantly increased urinary cGMP excretion.. The increasing efficacy of sampatrilat compared with lisinopril over 10 days could not be attributed to an increase in plasma ACE inhibition, suggesting that the NEP inhibitor activity of sampatrilat may have contributed to its antihypertensive action. NEP inhibition may enhance the antihypertensive effect of ACE inhibition.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Guanosine Monophosphate; Humans; Hypertension; Lisinopril; Male; Mesylates; Middle Aged; Neprilysin; Renin; Tyrosine

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

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Drugs, Investigational; Endopeptidases; Humans; Hypertension; Mesylates; Protease Inhibitors; Rats; Rats, Inbred SHR; Tyrosine