Synthesis and Biological Evaluation of Novel, Peripherally Selective Chromanyl Imidazolethione-Based Inhibitors of Dopamine β-Hydroxylase

Abstract

A novel series of dopamine beta-hydroxylase (DBH) inhibitors was designed and synthesized incorporating modifications to the core structure of nepicastat 3, with the principal aim of discovering potent DBH inhibitors exerting minimal effects on dopamine (DA) and noradrenaline (NA) levels in the central nervous system. This study resulted in the identification of a potent, peripherally selective DBH inhibitor, (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride 54 (BIA 5-453). In experiments in mice and rats at T(max) (9 h after administration), 54 reduced NA levels in a dose-dependent manner in both the left atrium and the left ventricle, with the maximal inhibitory effect attained at a dose of 100 mg/kg. In contrast to that found in the heart, 54 failed to affect NA tissue levels in the brain. Compound 54 is thus presented as a candidate for clinical evaluation for the treatment of chronic heart failure and hypertension.

New Approaches in the Treatment of Hypertension

“…110 Inhibition of DβH offers theoretical advantages over adrenergic receptor blockade: (1) it causes gradual sympathetic slowdown instead of acute inhibition and (2) it increases dopamine availability, thus causing renal vasodilation, natriuresis, and diuresis. First, second, and early third generations DβH inhibitors, for example, disulfiram, fusaric acid, and nepicastat, either lacked potency or selectivity for DβH or caused severe CNS-related adverse effects and thus were not clinically useful.…”

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

“…Associated genotypes were defined according to the literature. [17,24] Subjects were classified NAT1 rapid (fast) acetylators if they carried the NAT1 T > C, 590 G > A, and 857 G > A) and the corresponding genotypes determined. Associated genotypes were defined according to the literature.…”

“…[9,12,13] Several DbH inhibitors have been thus far reported; [14][15][16] however, both first-and secondgeneration DbH inhibitors were found to have low potency, poor DbH selectivity, and relevant toxic effects. [17] Nepicastat (RS-25560-197), [8] a third-generation DbH inhibitor, was found to have much greater potency and to be devoid of some of the problems associated with first-and second-generation inhibitors. However, nepicastat was found to cross the blood-brain barrier and to cause potentially significant CNS-related adverse events (AEs).…”

“…[17] Following oral administration of etamicastat, a blood pressurelowering effect was observed in studies performed with spontaneously hypertensive rats (SHR). Both the systolic and diastolic blood pressure (but not the heart rate) were decreased in SHR rats in a dose-dependent manner, an effect not observed in normotensive control rats.…”

Effect of Food on the Pharmacokinetic Profile of Etamicastat (BIA 5-453)

“…Etamicastat [BIA 5-453; (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride; molecular formula C14H16ClF2N3OS] was designed by BIAL-Portela & Co., S. Mamede do Coronado, Portugal, to act as a reversible inhibitor of peripheral DbH. [13] In contrast to that found in the peripheral tissues, etamicastat does not affect dopamine or noradrenaline levels in the brain, [13] which is unique among DbH inhibitors previously tested for the treatment of cardiovascular disorders.…”