etamicastat and Hypertension

Despite a large number of commercially available drugs, hypertension and related cardiovascular diseases remain a global problem. It is thus imperative that novel drugs and therapeutic strategies are regularly identified, and alternative targets explored. Dopamine β hydroxylase (DBH), a key player in the catecholamine biosynthetic pathway, may provide a therapeutic opportunity and should be extensively explored as a target for potent anti-hypertensives. Inhibitors of DBH have been successful in combating hypertension, as evidenced by the outcome of clinical trials for etamicastat and zamicastat.. We shed light on the strategies employed to identify inhibitors of the enzyme and outline the advantages that the target might offer. Structural and functional details of the enzyme are described along with specific methodologies for drug discovery that were never utilized for the therapeutic target.. Effective inhibitors of the enzyme may be identified with computer-aided structure-based design. Adoption of new methodologies and the assessment of newly designed inhibitors in DBH-specific animal models will provide new, safe, and cost-effective therapeutic opportunities.

Topics: Animals; Antihypertensive Agents; Benzopyrans; Dopamine beta-Hydroxylase; Drug Design; Drug Discovery; Enzyme Inhibitors; Humans; Hypertension; Imidazoles

Etamicastat is a dopamine β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure.. This study assessed the tolerability, pharmacokinetics, and pharmacodynamics of etamicastat in patients with arterial hypertension.. This randomized, double-blind, placebo-controlled study was conducted in male patients aged between 18 and 65 years with mild to moderate hypertension. Participants received once-daily doses of etamicastat 50, 100, or 200 mg or placebo for 10 days. Antihypertensive effect was assessed by 24-hour ambulatory blood pressure monitoring (ABPM).. The study enrolled 23 male volunteers, with ages between 49 and 64 years. There were no serious adverse events reported. All adverse events were mild to moderate in intensity and resolved without sequelae. Etamicastat Tmax was 1 hour postdose, and mean t½ was 19 to 28 hours following repeated administration. Etamicastat underwent N-acetylation by N-acetyltransferase 2 (NAT2), forming the metabolite BIA 5-961. Following repeated administration, mean etamicastat AUC was 2- to 3-fold greater in poor acetylators than in rapid acetylators. Approximately 50% of the etamicastat dose was recovered in urine-30% as unchanged etamicastat and 20% as BIA 5-961. Dose-dependent decreases in systolic and diastolic blood pressure were observed after 10 days of treatment. The mean (95% CI) decreases versus placebo in nighttime SBP were statistically significant with all 3 etamicastat doses (50 mg, -11.66 mm Hg [-21.57 to -1.76; P < 0.05]; 100 mg, -14.92 mm Hg [-24.98 to -4.87; P < 0.01]; and 200 mg, -13.62 mm Hg [-22.29 to -3.95; P < 0.01]).. Etamicastat was well tolerated and showed a pharmacokinetic profile consistent with a once-daily regimen. NAT2 phenotype markedly affected the pharmacokinetics. The antihypertensive effect of etamicastat, assessed by 24-hour ABPM, was dose dependent up to 100 mg. The assessment of etamicastat as a novel antihypertensive therapy requires further study in broader populations. EudraCT trial registration 2008-002789-09.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Arylamine N-Acetyltransferase; Benzopyrans; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Double-Blind Method; Heart Rate; Humans; Hypertension; Imidazoles; Isoenzymes; Male; Middle Aged; Phenotype; Young Adult

The aim of the present study was to evaluate the influence of chronic inhibition of dopamine ß-hydroxylase by etamicastat on the development of hypertension in the spontaneously hypertensive rat (SHR) and the sustainability of effects on the systolic and diastolic blood pressure in the SHR and the normotensive Wistar-Kyoto rat (WKY). WKY and SHR received etamicastat (10 mg/kg/d) from 5 weeks of age for 35 weeks in drinking water, and cardiovascular assessments were performed on a weekly basis. Etamicastat reduced systolic and diastolic blood pressure when SHRs reached the age of 16 weeks with mean decreases of 37 and 32 mm Hg, respectively, for the subsequent for 24 weeks of treatment, but did not prevent the increase in blood pressure (BP) aged between 5 and 11 week. The BP lowering effect of etamicastat in SHR was reversible on discontinuation and quickly resumed after reinstatement of therapy and was not accompanied by changes in heart rate. Etamicastat affected neither BP nor heart rate in WKY during 36 weeks of treatment. Etamicastat reduced urinary excretion of norepinephrine to a similar extent in WKY and SHR, accompanied by significant increases in urinary dopamine in SHR. Chronic administration of etamicastat did not adversely affected development of animals. Chronic dopamine ß-hydroxylase inhibition with etamicastat effectively decreases BP, although does not prevent the development of hypertension in the SHR.

Topics: Animals; Antihypertensive Agents; Benzopyrans; Blood Pressure; Disease Models, Animal; Dopamine beta-Hydroxylase; Enzyme Inhibitors; Heart Rate; Humans; Hypertension; Imidazoles; Male; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Hyperactivation of the sympathetic nervous system has an important role in the development and progression of arterial hypertension. This study evaluated the efficacy of etamicastat, a dopamine-β-hydroxylase (DβH) inhibitor, in controlling high blood pressure in the spontaneously hypertensive rat (SHR), either alone or in combination with other classes of antihypertensives. SHRs were administered with etamicastat by gavage, and its pharmacodynamic and pharmacokinetic properties were evaluated. Etamicastat induced a time-dependent decrease in noradrenaline-to-dopamine ratios in the heart and kidney, and had no effect on catecholamine levels in the frontal cortex of SHRs. Cardiovascular pharmacodynamic effects following administration of etamicastat alone or in combination with other classes of antihypertensive drugs were assessed by telemetry. Etamicastat was evaluated in combination with captopril, losartan, hydrochlorothiazide, metoprolol, prazosin and/or diltiazem. Etamicastat monotherapy induced a dose-dependent reduction in blood pressure without reflex tachycardia. Combination therapy amplified the antihypertensive effects of all tested drugs. In conclusion, inhibition of peripheral DβH with etamicastat, as a monotherapy or combination therapy, may constitute a valid alternative treatment for high blood pressure.

Topics: Animals; Antihypertensive Agents; Benzopyrans; Blood Pressure; Catecholamines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Hypertension; Imidazoles; Kidney; Male; Rats, Inbred SHR