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.