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A method of synthesis of 3-thiopropinyl derivatives of 5-oxo-1,3,4-benzothiadiazepine-4-acetic acid, potential antihypertensive drugs, vasopeptidase inhibitors, starting from 2-thiobenzoic acid hydrazide has been elaborated. [ABSTRACT FROM AUTHOR]

Hypertension is the most important cardiovascular risk factor. We have witnessed a significant improvement in hypertension treatment and control and an impressive growth in the pharmacologic options available to clinicians and hypertension specialists. With up to a third of patients with hypertension not at the recommended goal blood pressures, it is critically important to develop novel therapeutic approaches to better treat hypertension. This review will explore the ever-expanding horizon of antihypertensive treatment and will focus on 2 major areas of drug development. First, we will review novel targets for pharmacologic treatment and novel molecules and classes of drugs in various phases of development and recognize the limitations we face in their transition from research and development to clinical practice. Then, we will discuss an expanding array of combination strategies to better treat hypertension with the goal of minimizing the burden of cardiovascular and renal complications of hypertension. [ABSTRACT FROM AUTHOR]

Abstract: The potential of bovine lactoferrin (LF) as a source of antihypertensive peptides acting on the renin–angiotensin system (RAS) and the endothelin (ET) system as dual vasopeptidase inhibitors has been examined. For this purpose enzymatic LF hydrolyzates (LFHs) were generated by trypsin and proteinase K digestions. Permeate fractions with molecular masses lower than 3kDa (LFH <3kDa) were orally administered to spontaneously hypertensive rats (SHRs). Although both LFHs <3kDa showed in vitro angiotensin I-converting enzyme (ACE)-inhibitory activity, only proteinase K LFH <3kDa exerted an in vivo antihypertensive effect. The proteinase K LFH <3kDa and a previously characterized pepsin LFH <3kDa with ACE-inhibitory and antihypertensive effects were tested in ex vivo functional assays as inhibitors of ACE-dependent vasoconstriction. Pepsin LFH <3kDa but not proteinase K LFH <3kDa inhibited ACE-dependent vasoconstriction. When tested as inhibitors towards endothelin-converting enzyme (ECE), both LFHs <3kDa exerted in vitro inhibitory effects on ECE activity and inhibited ECE-dependent vasoconstriction. Most abundant peptides in proteinase K LFH <3kDa were identified by using an ion trap mass spectrometer. Based on peptide abundance, two peptides (GILRPY and REPYFGY) were chemically synthesized and their ECE-inhibitory activity was tested. Both exerted in vitro inhibitory effects on ECE activity. In conclusion, orally effective antihypertensive LFHs <3kDa may act as dual vasopeptidase (ACE/ECE) or as single ECE inhibitors with different antivasoconstrictor effects depending on the protease used to release bioactive peptide sequences. [Copyright &y& Elsevier]

Despite the many therapeutic options available today for the treatment of hypertension, a large number of patients remain uncontrolled. The classic antihypertensive therapies including β-blockers, diuretics, calcium channel blockers and the wide class of renin--angiotensin--aldosterone system blockers (converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and mineralocorticoid receptor blockers), are variably successful in achieving the target blood pressure values in hypertensive patients. Although these numerous, safe and effective pharmacologic therapies are available to treat hypertension, novel therapeutic approaches are warranted to improve the management and prognosis of patients with this condition. Several lines of research suggest promising results based on novel pharmacologic and device-based approaches that may treat effectively resistant hypertension and target organ damage in the future. A large number of the new therapeutic strategies are related to renin angiotensin aldosterone system (RAAS). Modulation of the RAAS provides the rationale for current new antihypertensive drugs already used in clinical practice, including eplerenone and aliskiren. The combined angiotensin-converting-enzyme and neutral endopeptidase blockade decreases blood pressure, aldosterone synthase inhibitors improve tolerability in aldosterone antagonism, prorenin-receptor blockers could prevent the angiotensin-independent actions of renin. In the past few years new minimally invasive surgical procedures like carotid baroreceptor activation and renal symphatetic denervation were developed and could be a therapeutic option for patients with uncontrolled hypertension. [ABSTRACT FROM AUTHOR]

Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102±2 to 181±12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189±3 mm Hg) or omapatrilat (184±8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6±0.2 vs. 0.5±0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9±0.4 pmol/day) compared to enalapril-treated (1.6±0.2 pmol/day) or untreated (1.5±0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production. [Copyright &y& Elsevier]

Abstract The bradykinin-potentiating peptides from Bothrops jararaca venom are the most potent natural inhibitors of the angiotensin-converting enzyme. The biochemical and biological features of these peptides were crucial to demonstrate the pivotal role of the angiotensin-converting enzyme in blood pressure regulation. In the present study, seven bradykinin-potentiating peptides were identified within the C-type natriuretic peptide precursor cloned from snake brain. The bradykinin-potentiating peptides deduced from the B. jararaca brain precursor are strong in vitro inhibitors of the angiotensin-converting enzyme (nanomolar range), and also potentiate the bradykinin effects in ex vivo and in vivo experiments. Two of these peptides are novel bradykinin-potentiating peptides, one of which displays high specificity toward the N-domain active site of the somatic angiotensin-converting enzyme. In situ hybridization studies revealed the presence of the bradykinin-potentiating peptides precursor mRNAs in distinct regions of the B. jararaca brain, such as the ventromedial hypothalamus, the paraventricular nuclei, the paraventricular organ, and the subcommissural organ. The biochemical and pharmacological properties of the brain bradykinin-potentiating peptides, their presence within the neuroendocrine regulator C-type natriuretic peptide precursor, and their expression in regions of the snake brain correlated to neuroendocrine functions, strongly suggest that these peptides belong to a novel class of endogenous vasoactive peptides. [ABSTRACT FROM AUTHOR]

Considerable attention has recently focused on the vasopeptidase inhibitors (VPI), a new class of drug that combines angiotensin-converting enzyme (ACE) inhibitor activity with inhibition of natriuretic peptide breakdown. In theory, a drug with these properties may be beneficial both in hypertension and in heart failure. Whilst the efficacy of VPIs in hypertension has been consistently demonstrated in pre-clinical and clinical studies, the role of VPIs, if any, in heart failure is less clear, since numerous small studies have produced conflicting results. Furthermore, preliminary results from the recently completed Omapatrilat Versus Enalapril Randomised Trial of Utility in Reducing Events (OVERTURE) study have failed to establish the VPI, omapatrilat, as a first line therapy in the treatment of chronic heart failure. We review the literature on VPIs in heart failure and discuss possible reasons for the reported lack of benefit over ACE inhibitors. [ABSTRACT FROM PUBLISHER]

Vasopeptidase inhibitors are a new class of drugs that have dual inhibitory effects on two key enzymes involved in the metabolism of vasoactive peptides. Essentially, they inhibit angiotensin-converting enzyme (ACE), thereby blocking the generation of angiotensin II (Ang II); at the same time they prevent the breakdown of natriuretic peptides by the enzyme neutral endopeptidase. The combination of reduction of Ang II on a background of increased natriuretic peptide activity has several potential advantages for the treatment of cardiovascular and renal disease and in particular, hypertension and congestive heart failure (CHF). Several vasopeptidase inhibitors, such as sampatrilat, fasidotril, gemopatrilat and omapatrilat (VanlevTM, the most clinically developed vasopeptidase inhibitor to date) are under intensive clinical investigation. Recent clinical trials have demonstrated effective antihypertensive activity in hypertension, independent of age, renin and salt status or ethnic origin, and have also highlighted the potential for vasopeptidase inhibition as a new therapeutic modality for the treatment of CHF. Moreover, ongoing research suggests that this new class of drugs may be an important approach, not only for the treatment of hypertension and of conditions associated with overt volume overload but also for ischaemic heart disease. [ABSTRACT FROM PUBLISHER]

Objective: The pharmacodynamics and pharmacokinetics of omapatrilat, a member of a new class of cardiovascular compounds, the vasopeptidase inhibitors, were evaluated in subjects with hepatic cirrhosis (n=10) and in healthy subjects (n=10) matched for age, weight, gender and smoking history. Methods: All subjects received omapatrilat 25 mg orally once daily for 14 days. Plasma renin and urinary atrial natriuretic peptide (ANP) levels were measured to assess the effect of omapatrilat on cirrhotic subjects. The effect of omapatrilat on blood pressure as well as changes in ANP and plasma renin levels were not altered by hepatic impairment. Pharmacokinetic parameters were determined from plasma omapatrilat concentrations. Results: There were no significant differences between the two subject groups with regard to log-transformed area under the curve or maximum observed plasma concentration. Systemic accumulation was similar in the two groups. Conclusion: These results suggest, based on findings in otherwise healthy cirrhotic subjects, that no adjustment of standard dosing regimens is indicated for hypertensive patients with mild to moderate cirrhosis. [ABSTRACT FROM AUTHOR]