title: Etamicastat, a new dopamine-ß-hydroxylase inhibitor, pharmacodynamics and metabolism in rat.
abstract: Despite the importance of sympathetic nervous system in pathophysiological mechanisms of cardiac heart failure and essential hypertension, therapy specifically targeting the sympathetic nervous system is currently underutilized. Etamicastat is a novel dopamine-ß-hydroxylase (DBH) inhibitor that is oxidized into BIA 5-965 and deaminated followed by oxidation to BIA 5-998, which represents 13% of total etamicastat and quantified metabolites. However, the primary metabolic pathway of etamicastat in rats was found to be the N-acetylation (BIA 5-961), which represents 44% of total etamicastat and quantified metabolites. Trace amounts of BIA 5-961 de-sulfated and S-glucuronide were also detected. All the main metabolites of etamicastat inhibited DBH with IC50 values of 306 (228, 409), 629 (534, 741), 427 (350, 522) nM for BIA 5-965, BIA 5-998 and BIA 5-961, respectively. However, only etamicastat (IC50 of 107 (94; 121) nM) was able to reduce catecholamine levels in sympathetic nervous system innervated peripheral tissues, without effect upon brain catecholamines. Quantitative whole body autoradiography revealed a limited transfer of etamicastat related radioactivity to brain tissues and the mean recovery of radioactivity was ~90% of the administered radioactive dose, eliminated primarily via renal excretion over 5 days. The absolute oral bioavailability of etamicastat was 64% of the administered dose. In conclusion, etamicastat is a peripheral selective DBH inhibitor mainly N-acetylated in the aminoethyl moiety and excreted in urine. Etamicastat main metabolites inhibit DBH, but only etamicastat demonstrated unequivocal pharmacological effects as a DBH inhibitor with impact upon the activity of the sympathetic nervous system under in vivo conditions.
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457S Mamede do Coronado, Portugal.
authors: Ana I
authors: AI
authors: Loureiro
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457S Mamede do Coronado, Portugal.
authors: Maria João
authors: MJ
authors: Bonifácio
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457S Mamede do Coronado, Portugal.
authors: Carlos
authors: C
authors: Fernandes-Lopes
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457S Mamede do Coronado, Portugal.
authors: Bruno
authors: B
authors: Igreja
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457S Mamede do Coronado, Portugal.
authors: Lyndon C
authors: LC
authors: Wright
authors: Department of Research and Development, BIAL - Portela & Cª, S.A., 4745-457S Mamede do Coronado, Portugal; Department of Pharmacology and Therapeutic, Faculty of Medicine, Porto, Portugal. Electronic address: psoares.silva@bial.com.
authors: Patrício
authors: P
authors: Soares-da-Silva
mesh_terms: D000107:Acetylation; D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D001578:Benzopyrans / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine; D005243:Feces / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011994:Recombinant Proteins; C509002:etamicastat; D004299:Dopamine beta-Hydroxylase; D014453:Glucuronosyltransferase; D004298:Dopamine; D009638:Norepinephrine
keywords: Distribution; Dopamine-ß-hydroxylase; Etamicastat; Metabolism