Beliaev Alexandre, Learmonth David A, Soares-da-Silva Patricio
Laboratories of Chemistry and Pharmacology, Department of Research & Development, BIAL, 4745-457 S. Mamede do Coronado, Portugal.
J Med Chem. 2006 Feb 9;49(3):1191-7. doi: 10.1021/jm051051f.
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.
设计并合成了一系列新型多巴胺β-羟化酶（DBH）抑制剂，这些抑制剂对奈匹西他3的核心结构进行了修饰，主要目的是发现对中枢神经系统中多巴胺（DA）和去甲肾上腺素（NA）水平影响最小的强效DBH抑制剂。本研究鉴定出一种强效的外周选择性DBH抑制剂，即（R）-5-（2-氨基乙基）-1-（6,8-二氟苯并二氢吡喃-3-基）-1,3-二氢咪唑-2-硫酮盐酸盐54（BIA 5-453）。在小鼠和大鼠的实验中，在给药后9小时的T(max)时，54以剂量依赖性方式降低左心房和左心室中的NA水平，在剂量为100 mg/kg时达到最大抑制效果。与在心脏中发现的情况相反，54未能影响脑中的NA组织水平。因此，化合物54被作为治疗慢性心力衰竭和高血压的临床评估候选药物。
