rb-150 and Hypertension

Hypertension significantly increases the risk of cardiovascular disease. Currently, effective standard pharmacological treatment is available in the form of diuretics, ACE inhibitors, angiotensin II receptor blockers and calcium channel blockers. These all help to decrease blood pressure in hypertensive patients, each with their own mechanism. Recently, firibastat, a new first-in-class antihypertensive drug has been developed. Firibastat is a prodrug that when crossing the blood-brain barrier, is cleaved into two active EC33 molecules. EC33 is the active molecule that inhibits the enzyme aminopeptidase A. Aminopeptidase A converts angiotensin II to angiotensin III. Angiotensin III usually has three central mechanisms that increase blood pressure, so by inhibiting this enzyme activity, a decrease in blood pressure is seen. Firibastat is an antihypertensive drug that affects the brain renin angiotensin system by inhibiting aminopeptidase A. Clinical trials with firibastat have been performed in animals and humans. No severe adverse effects related to firibastat treatment have been reported. Results from studies show that firibastat is generally well tolerated and safe to use in hypertensive patients. The aim of this review is to investigate the current knowledge about firibastat in the treatment of hypertension.

Topics: Animals; Arteries; Clinical Trials as Topic; Disulfides; Humans; Hypertension; Prodrugs; Renin-Angiotensin System; Sulfonic Acids

Global incidence and prevalence of hypertension continues to increase and remains a significant challenge. The ever-increasing number of cases are due to comorbid conditions such as obesity and diabetes, as well as lifestyle indiscretions such as excessive salt intake. Hypertension, congestive heart failure, and kidney disease are all conditions resulting from abnormal Renin-Angiotensin-Aldosterone activation and adverse remodeling. Firibastat, a novel Brain Aminopeptidase inhibitor, may be able to help achieve blood pressure control in those with resistant hypertension. In this review article, we will discuss the biochemical pathway of firibastat and various trials assessing drug efficacy in animals and humans. This drug has the potential to curb the risk of uncontrolled hypertension and help improve long term cardiovascular morbidity and mortality.

Topics: Aminopeptidases; Animals; Antihypertensive Agents; Brain; Disulfides; Humans; Hypertension; Renin-Angiotensin System; Sulfonic Acids

The purpose of this review is to discuss the unique mechanism of firibastat, a new antihypertension medication. Hypertension continues to be a highly prevalent public health issue.. Firibastat is a novel agent developed to treat hypertension. As the first member in the class of centrally acting agents to target the brain renin angiotensin system, firibastat offers new pathways to consider and enhances the regimen of agents currently available to treat hypertension. Recent clinical trials have demonstrated effectiveness and safety in mild hypertension as well as resistant hypertension. This review introduces firibastat as a new therapeutic class of treatment for hypertension focused on the renin angiotensin system in the brain. Early studies have shown a significant reduction in blood pressure with minimal side effects particularly in patients who are difficult to treat.

Topics: Antihypertensive Agents; Blood Pressure; Disulfides; Glutamyl Aminopeptidase; Humans; Hypertension; Renin-Angiotensin System; Sulfonic Acids

The pathophysiology of heart failure (HF) and hypertension are thought to involve brain renin-angiotensin system (RAS) hyperactivity. Angiotensin III, a key effector peptide in the brain RAS, provides tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme responsible for generating brain angiotensin III, constitutes a potential therapeutic target for hypertension treatment. We focus here on studies of RB150/firibastat, the first prodrug of the specific and selective APA inhibitor EC33 able to cross the blood-brain barrier. We consider its development from therapeutic target discovery to clinical trials of the prodrug. After oral administration, firibastat crosses the gastrointestinal and blood-brain barriers. On arrival in the brain, it is cleaved to generate EC33, which inhibits brain APA activity, lowering BP in various experimental models of hypertension. Firibastat was clinically and biologically well tolerated, even at high doses, in phase I trials conducted in healthy human subjects. It was then shown to decrease BP effectively in patients of various ethnic origins with hypertension in phase II trials. Brain RAS hyperactivity leads to excessive sympathetic activity, which can contribute to HF after myocardial infarction (MI). Chronic treatment with oral firibastat (4 or 8 weeks after MI) has been shown to normalize brain APA activity in mice. This effect is accompanied by a normalization of brain RAS and sympathetic activities, reducing cardiac fibrosis and hypertrophy and preventing cardiac dysfunction. Firibastat may therefore represent a novel therapeutic advance in the clinical management of patients with hypertension and potentially with HF after MI.

Topics: Angiotensin II; Angiotensin III; Animals; Antihypertensive Agents; Brain; Clinical Trials as Topic; Disulfides; Glutamyl Aminopeptidase; Heart Failure; Humans; Hypertension; Myocardial Infarction; Renin-Angiotensin System; Sulfonic Acids

Hypertension affects one-third of the adult population and is a growing problem due to the increasing incidence of obesity and diabetes. Brain RAS (renin-angiotensin system) hyperactivity has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We have identified in the brain RAS that APA (aminopeptidase A) and APN (aminopeptidase N), two membrane-bound zinc metalloproteases, are involved in the metabolism of AngII (angiotensin II) and AngIII (angiotensin III) respectively. The present review summarizes the main findings suggesting that AngIII plays a predominant role in the brain RAS in the control of BP (blood pressure). We first explored the organization of the APA active site by site-directed mutagenesis and molecular modelling. The development and the use in vivo of specific and selective APA and APN inhibitors EC33 and PC18 respectively, has allowed the demonstration that brain AngIII generated by APA is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over BP in conscious hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, which has led to the development of potent orally active APA inhibitors, such as RB150. RB150 administered orally in hypertensive DOCA (deoxycorticosteroneacetate)-salt rats or SHRs (spontaneously hypertensive rats) crosses the intestinal, hepatic and blood-brain barriers, enters the brain, generates two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and normalize BP for several hours. The decrease in BP involves two different mechanisms: a decrease in vasopressin release into the bloodstream, which in turn increases diuresis resulting in a blood volume reduction that participates in the decrease in BP and/or a decrease in sympathetic tone, decreasing vascular resistance. RB150 constitutes the prototype of a new class of centrally acting antihypertensive agents and is currently being evaluated in a Phase Ib clinical trial.

Topics: Angiotensin III; Animals; Binding Sites; Blood Pressure; Blood-Brain Barrier; Brain; Clinical Trials, Phase I as Topic; Disulfides; Drug Design; Glutamyl Aminopeptidase; Humans; Hypertension; Models, Molecular; Mutagenesis, Site-Directed; Protease Inhibitors; Rats; Sulfonic Acids

Among the main bioactive peptides of the brain renin-angiotensin system, angiotensin (Ang) II and AngIII exhibit the same affinity for the type 1 and type 2 Ang receptors. Both peptides, injected intracerebroventricularly, cause similar increase in blood pressure (BP). Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarized recent insights into the predominant role of brain AngIII in the central control of BP underlining the fact that brain aminopeptidase A (APA), the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension. This led to the development of potent, systematically active APA inhibitors, such as RB150, as a prototype of a new class of centrally acting antihypertensive agents for the treatment of certain forms of hypertension.

Topics: Angiotensin II; Angiotensin III; Animals; Antihypertensive Agents; Disulfides; Enzyme Inhibitors; Glutamyl Aminopeptidase; Hypertension; Models, Biological; Renin-Angiotensin System; Sulfonic Acids

We conducted a pilot multicenter double-blind randomized placebo-controlled crossover pharmacodynamic study to evaluate the blood pressure (BP) and the hormonal effects of firibastat, a first-in-class aminopeptidase A inhibitor prodrug, in patients with hypertension.. Thirty-four patients with daytime ambulatory BP of at least 135/85 mmHg and less than 170/105 mmHg, after a 2-week run-in period were randomly assigned to receive either firibastat (250 mg b.i.d. for 1 week uptitrated to 500 mg b.i.d. for 3 weeks) and then placebo for 4 weeks each or vice versa, with a 2-week washout period on placebo.. At 4 weeks, daytime ambulatory systolic BP (SBP) decreased by 2.7 mmHg (95% confidence interval -6.5 to +1.1 mmHg) with firibastat versus placebo (P = 0.157). Office SBP decreased by 4.7 mmHg (95% confidence interval -11.1 to +1.8 mmHg) with firibastat versus placebo (P = 0.151). However, more the basal daytime ambulatory SBP was elevated, more the firibastat-induced BP decrease was marked. Firibastat did not influence 24h-ambulatory heart rate. Firibastat had no effect on plasma renin, aldosterone, apelin and copeptin concentrations. No major adverse events occurred. There was one episode of reversible skin allergy with facial edema.. In patients with hypertension, a 4-week treatment with firibastat, tended to decrease daytime SBP relative to placebo. Firibastat did not modify the activity of the systemic renin-angiotensin system These results have justified designing a larger, powered trial of longer duration to fully assess its safety and effectiveness.. http://www.clinicaltrials.gov. NCT02322450.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Disulfides; Double-Blind Method; Female; Glutamyl Aminopeptidase; Humans; Hypertension; Male; Middle Aged; Pilot Projects; Renin-Angiotensin System; Sulfonic Acids; Young Adult

In the brain, aminopeptidase A (APA), a membrane-bound zinc metalloprotease, generates angiotensin III from angiotensin II. Brain angiotensin III exerts a tonic stimulatory effect on the control of blood pressure (BP) in hypertensive rats and increases vasopressin release. Blocking brain angiotensin III formation by the APA inhibitor prodrug RB150/firibastat normalizes arterial BP in hypertensive deoxycorticosterone acetate (DOCA)-salt rats without inducing angiotensin II accumulation. We therefore hypothesized that another metabolic pathway of brain angiotensin II, such as the conversion of angiotensin II into angiotensin 1-7 (Ang 1-7) by angiotensin-converting enzyme 2 (ACE2) might be activated following brain APA inhibition. We found that the intracerebroventricular (icv) administration of RB150/firibastat in conscious DOCA-salt rats both inhibited brain APA activity and induced an increase in brain ACE2 activity. Then, we showed that the decreases in BP and vasopressin release resulting from brain APA inhibition with RB150/firibastat were reduced if ACE2 was concomitantly inhibited by MLN4760, a potent ACE2 inhibitor, or if the Mas receptor (MasR) was blocked by A779, a MasR antagonist. Our findings suggest that in the brain, the increase in ACE2 activity resulting from APA inhibition by RB150/firibastat treatment, subsequently increasing Ang 1-7 and activating the MasR while blocking angiotensin III formation, contributes to the antihypertensive effect and the decrease in vasopressin release induced by RB150/firibastat. RB150/firibastat treatment constitutes an interesting therapeutic approach to improve BP control in hypertensive patients by inducing in the brain renin-angiotensin system, hyperactivity of the beneficial ACE2/Ang 1-7/MasR axis while decreasing that of the deleterious APA/Ang II/Ang III/ATI receptor axis.

Topics: Angiotensin III; Angiotensin-Converting Enzyme 2; Animals; Antihypertensive Agents; Brain; Desoxycorticosterone Acetate; Disease Models, Animal; Disulfides; Glutamyl Aminopeptidase; Hypertension; Male; Mice; Rats, Wistar; Sodium Chloride, Dietary; Sulfonic Acids

In the brain, aminopeptidase A (APA) generates angiotensin III, one of the effector peptides of the brain renin-angiotensin system (RAS), exerting tonic stimulatory control over blood pressure (BP) in hypertensive rats. Oral administration of firibastat, an APA inhibitor prodrug, in hypertensive rats, inhibits brain APA activity, blocks brain angiotensin III formation and decreases BP. In this study, we evaluated the efficacy of firibastat in combination with enalapril, an angiotensin I-converting enzyme inhibitor, and hydrochlorothiazide (HCTZ), in conscious hypertensive deoxycorticosterone acetate (DOCA)-salt rats, which display high plasma arginine-vasopressin levels, low circulating renin levels and resistance to treatment by systemic RAS blockers. We determined mean arterial BP, heart rate, plasma arginine-vasopressin levels and renin activity in DOCA-salt rats orally treated with firibastat, enalapril or HCTZ administered alone or in combination. Acute oral firibastat administration (30 mg/kg) induced a significant decrease in BP, whereas enalapril (10 mg/kg) or HCTZ (10 mg/kg) administered alone induced no significant change in BP in conscious DOCA-salt rats. The BP decrease induced by acute and nine-day chronic tritherapy [Firibastat+Enalapril+HCTZ] was significantly greater than that observed after bitherapy [Enalapril+HCTZ]. Interestingly, the chronic administration of a combination of firibastat with [Enalapril+HCTZ] reduced plasma arginine-vasopressin levels by 62% relative to those measured in DOCA-salt rats receiving bitherapy. Our data show that tritherapy with firibastat, enalapril and HCTZ improves BP control and arginine-vasopressin release in an experimental salt-dependent model of hypertension, paving the way for the development of new treatments for patients with currently difficult-to-treat or resistant hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Desoxycorticosterone Acetate; Disease Models, Animal; Disulfides; Enalapril; Glutamyl Aminopeptidase; Hydrochlorothiazide; Hypertension; Male; Rats; Rats, Inbred WKY; Renin-Angiotensin System; Sulfonic Acids; Vasopressins

Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We have shown that aminopeptidase A is involved in the formation of brain angiotensin III, which exerts tonic stimulatory control over blood pressure in hypertensive deoxycorticosterone acetate-salt rats and spontaneously hypertensive rats. We have also shown that injection of the specific and selective aminopeptidase A inhibitor, (3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid (EC33), by central route or its prodrug, RB150/firibastat, by oral route inhibited brain aminopeptidase A activity and blocked the formation of brain angiotensin III, normalizing blood pressure in hypertensive rats. These findings identified brain aminopeptidase A as a potential new therapeutic target for hypertension. We report here the development of a new aminopeptidase A inhibitor prodrug, NI956/QGC006, obtained by the disulfide bridge-mediated dimerization of NI929. NI929 is 10× more efficient than EC33 at inhibiting recombinant mouse aminopeptidase A activity in vitro. After oral administration at a dose of 4 mg/kg in conscious deoxycorticosterone acetate-salt rats, NI956/QGC006 normalized brain aminopeptidase A activity and induced a marked decrease in blood pressure of -44±13 mm Hg 4 hours after treatment ( P<0.001), sustained over 10 hours (-21±12 mm Hg; P<0.05). Moreover, NI956/QGC006 decreased plasma arginine-vasopressin levels, and increased diuresis and natriuresis, that may participate to the blood pressure decrease. Finally, NI956/QGC006 did not affect plasma sodium and potassium concentrations. This study shows that NI956/QGC006 is a best-in-class central-acting aminopeptidase A inhibitor prodrug. Our results support the development of hypertension treatments targeting brain aminopeptidase A.

Topics: Animals; Blood Pressure; Brain; Disease Models, Animal; Disulfides; Glutamyl Aminopeptidase; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; Sulfonic Acids

Hyperactivity of the brain renin-angiotensin (Ang) system has been implicated in the development and maintenance of hypertension. AngIII, one of the main effector peptides of the brain renin-Ang system, exerts a tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme generating brain AngIII, represents a new therapeutic target for the treatment of hypertension. We developed RB150, a prodrug of the specific and selective APA inhibitor, EC33. When given orally in acute treatment in hypertensive rats, RB150 crosses the gastrointestinal and blood-brain barriers, enters the brain, inhibits brain APA activity and decreases BP. We investigate, here, the antihypertensive effects of chronic oral RB150 (50 mg/kg per day) treatment over 24 days in alert hypertensive deoxycorticosterone acetate-salt rats.. We measured variations in Brain APA enzymatic activity, SBP, plasma arginine vasopressin levels and metabolic parameters after RB150 chronic administration.. This resulted in a significant decrease in SBP over the 24-day treatment period showing that no tolerance to the antihypertensive RB150 effect was observed throughout the treatment period. Chronic RB150 treatment also significantly decreased plasma arginine vasopressin levels and increased diuresis, which participate to BP decrease by reducing the size of fluid compartment. Interestingly, we observed an increased natriuresis without modifying both plasma sodium and potassium levels.. Our results strengthen the interest of developing RB150 as a novel central-acting antihypertensive agent and evaluating its efficacy in salt-sensitive hypertension.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Arginine Vasopressin; Blood Pressure; Brain; Desoxycorticosterone Acetate; Disulfides; Enzyme Inhibitors; Glutamyl Aminopeptidase; Hypertension; Male; Natriuresis; Rats; Sulfonic Acids

Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We reported previously in the brain that aminopeptidase A and aminopeptidase N are involved in the metabolism of angiotensin II and angiotensin III, respectively. By using in vivo specific and selective aminopeptidase A and aminopeptidase N inhibitors, we showed that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting a tonic stimulatory control more than blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential target for the treatment of hypertension. We demonstrated here the antihypertensive effects of RB150, a prodrug of the specific and selective aminopeptidase A inhibitor, EC33, in spontaneously hypertensive rats, a model of human essential hypertension. Oral administration of RB150 in conscious spontaneously hypertensive rats inhibited brain aminopeptidase A activity, demonstrating the central bioavailability of RB150 and its ability to generate EC33 into the brain. Oral RB150 treatment dose-dependently reduced blood pressure in spontaneously hypertensive rats with an ED(50) of 30 mg/kg, lasting for several hours. This decrease in blood pressure is partly attributed to a decrease in sympathetic tone, reducing vascular resistance. This treatment did not modify systemic renin-angiotensin system activity. Concomitant oral administration of RB150 with a systemic renin-angiotensin system blocker, enalapril, potentiated the RB150-induced blood pressure decrease achieved in <2 hours. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents that might be used in combination with classic systemic renin-angiotensin system blockers to improve blood pressure control.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Brain; Disease Models, Animal; Disulfides; Dose-Response Relationship, Drug; Enalapril; Enzyme Inhibitors; Glutamyl Aminopeptidase; Heart Rate; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; Sulfonic Acids

Overactivity of the brain renin-angiotensin system has been implicated in the development and maintenance of hypertension. We reported previously that angiotensin II is converted to angiotensin III by aminopeptidase A in the mouse brain. We then used specific and selective aminopeptidase A inhibitors to show that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting tonic stimulatory control over blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential candidate central nervous system target for the treatment of hypertension. Given this possible clinical use of aminopeptidase A inhibitors, it was, therefore, important to investigate their pharmacological activity after oral administration. We investigated RB150, a dimer of the selective aminopeptidase A inhibitor, EC33, generated by creating a disulfide bond. This chemical modification allows prodrug to cross the blood-brain barrier when administered by systemic route. Oral administration of RB150 in conscious DOCA-salt rats inhibited brain aminopeptidase A activity, resulting in values similar to those obtained with the brains of normotensive rats, demonstrating the central bioavailability of RB150. Oral RB150 treatment resulted in a marked dose-dependent reduction in blood pressure in DOCA-salt but not in normotensive rats, with an ED(50) in the 1-mg/kg range, achieved in <2 hours and lasting for several hours. This treatment also significantly decreased plasma arginine-vasopressin levels and increased diuresis, which may participate to the blood pressure decrease by reducing the size of fluid compartment. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents.

Topics: Administration, Oral; Animals; Arginine Vasopressin; Blood Pressure; Disease Models, Animal; Disulfides; Diuresis; Drinking; Enzyme Inhibitors; Glutamyl Aminopeptidase; Hypertension; Male; Rats; Rats, Inbred Dahl; Rats, Inbred WKY; Sulfonic Acids