Dopamine &amp;#946;-Monooxygenase: Mechanism, Substrates and Inhibitors

Беляев, А. Н.; Ferreira, Humberto; Learmonth, David A.; Soares-da-Silva, Patrı́cio

doi:10.2174/157340809787314265

Cited by 28 publications

(31 citation statements)

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“…This is in agreement with other studies showing that imidazol-2-thione derivatives are endowed with nanomolar potency in inhibiting DBH actvity (Beliaev et al, 2009;Kruse et al, 1987). Nevertheless, these compounds fail to decrease catecholamine levels in sympathetically innervated tissue in the mouse following intraperitoneal administration (100 mg/kg).…”

Section: Discussionsupporting

confidence: 92%

Etamicastat, a new dopamine-ß-hydroxylase inhibitor, pharmacodynamics and metabolism in rat

Loureiro

Bonifácio

Fernandes-Lopes

et al. 2014

European Journal of Pharmacology

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Section: Discussionsupporting

confidence: 92%

Etamicastat, a new dopamine-ß-hydroxylase inhibitor, pharmacodynamics and metabolism in rat

Loureiro

Bonifácio

Fernandes-Lopes

et al. 2014

European Journal of Pharmacology

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“…Several inhibitors of this enzyme have been developed (Beliaev et al, 2009), none achieving marketing approval because of weak potency, poor DBH selectivity and/or significant adverse effects (Beliaev et al, 2009;Kruse et al, 1986b). Etamicastat (Fig.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-β-hydroxylase: Comparison with nepicastat

Bonifácio

Sousa

Neves

et al. 2015

European Journal of Pharmacology

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“…In parallel, the urinary excretion of dopamine increased significantly but only in SHR rats. [20] Etamicastat safety, tolerability, and pharmacokinetics were investigated in a previous entryinto-man single-dose, double-blind, randomized, placebo-controlled study in healthy subjects in the dose range 2-1200 mg. [21] Maximum plasma concentrations (C max ) occurred at 1-3 hours after dosing. Elimination was bi-compartmental, characterized by a first short early elimination half-life (t ½ ) followed by a longer t ½ of 16-20 hours for etamicastat doses ‡100 mg.…”

Section: Introductionmentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor, in a Rising Multiple-Dose Study in Young Healthy Subjects

et al. 2010

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Background: Activation of the sympathetic nervous system is an important feature in hypertension and congestive heart failure. A strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of norepinephrine (noradrenaline) via inhibition of dopamine-b-hydroxylase (DbH). Objective: To assess the safety, tolerability, and pharmacokinetics of etamicastat (BIA 5-453), a new DbH inhibitor, following repeated dosing. Methods: A double-blind, randomized, placebo-controlled study was conducted in healthy young male volunteers. Participants received once-daily doses of placebo or etamicastat 25, 50, 100, 200, 400, or 600 mg, for 10 days. Results: Etamicastat underwent N-acetylation to its metabolite BIA 5-961. Etamicastat and BIA 5-961 maximum concentrations were achieved at 1-3 and 2-4 hours, respectively, after dosing. Elimination half-lives ranged from 18.1 to 25.7 hours for etamicastat and 6.7 to 22.5 hours for BIA 5-961. Both etamicastat and BIA 5-961 followed linear pharmacokinetics. The extent of systemic exposure to etamicastat and BIA 5-961 increased in an approximately dose-proportional manner, and steady-state plasma concentrations were attained up to 9 days of dosing. Etamicastat accumulated in plasma following repeated administration. The mean observed accumulation ratio was 1.3-1.9 for etamicastat and 1.3-1.6 for BIA 5-961. Approximately 40% of the etamicastat dose was recovered in urine in the form of parent compound and BIA 5-961. There was a high variability in pharmacokinetic parameters, attributable to different N-acetyltransferase-2 (NAT2) phenotype. Urinary excretion of norepinephrine decreased following repeated administration of etamicastat. Etamicastat was generally well tolerated. There was no serious

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Dopamine β-Monooxygenase: Mechanism, Substrates and Inhibitors

Cited by 28 publications

References 0 publications

Etamicastat, a new dopamine-ß-hydroxylase inhibitor, pharmacodynamics and metabolism in rat

Etamicastat, a new dopamine-ß-hydroxylase inhibitor, pharmacodynamics and metabolism in rat

Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-β-hydroxylase: Comparison with nepicastat

Safety, Tolerability, and Pharmacokinetics of Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor, in a Rising Multiple-Dose Study in Young Healthy Subjects

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