Friehe H, Ney P
Department of Pharmacology and Toxicology, Schwarz Pharma AG, Monheim, Germany.
Arzneimittelforschung. 1997 Feb;47(2):132-44.
The pharmacodynamic and toxicological profile of the new angiotensin converting enzyme (ACE) inhibitor moexipril (CAS 82586-52-5) and its active diacid metabolite moexiprilat were studied in vitro as well as in vivo. In vitro, moexiprilat was a potent inhibitor of ACE in guinea pig serum as well as on purified ACE from rabbit lung with IC50 values of 2.6 and 4.9 nmol/l, respectively. Both, moexipril and moexiprilat inhibited the angiotensin I (ANG I)-induced contractions of rabbit aorta concentration-dependently, whereas contractions by other agents were not affected, indicating a high selectivity of both compounds for ACE. Similar results were obtained in vivo in experiments investigating the blood pressure increasing response to intravenous injection of ANG I or ANG II in conscious normotensive rats and dogs after oral or intravenous application of moexipril or moexiprilat, respectively. The antihypertensive effects of the oral application of moexipril were studied in models of hypertension in the rat as well as in renal hypertensive dogs. In renal hypertensive rats, moexipril (0.03-10 mg/kg p.o.) caused a dose-dependent decrease in blood pressure with a threshold dose of 0.3 mg/kg. Once daily treatment of the animals with 3 mg/kg/d for 5 days lowered mean blood pressure by about 70 mmHg and blood pressure was maintained on this low level for the experimental period. In spontaneously hypertensive rats, oral administration of moexipril (30 mg/kg/d) for 5 days caused a progressive lowering of mean blood pressure from pre-treatment values of 180 +/- 7 mmHg to a trough on day 4 of 127 +/- 4 mmHg. In perinephritic hypertensive dogs, oral administration of moexipril (10 mg/kg) in combination with hydrochlorothiazide (10 mg/kg) caused a drop of mean blood pressure by 25 mmHg from pre-treatment control, which persisted for 24 h. In all these models, the action was characterized by a rapid onset and a long duration of action. After cessation of treatment, a gradual return to baseline values was observed. In contrast, only slight blood pressure lowering effects were seen in normotensive rats at high doses (100 mg/kg p.o.). The general pharmacological properties of moexipril were also studied in generally accepted models in vitro and in vivo. In doses or concentrations more than 100 times higher than those causing ACE inhibition, no effects were observed on the central nervous system, on isolated smooth muscle preparations, the digestive system, the kidney or the lung. Additionally, moexipril is devoid of anti-inflammatory properties and has no effect on platelet function. On the cardiovascular system, the effects observed can be attributed to ACE inhibition by moexipril. Repeated dose toxicity studies in rats and dogs revealed the heart and kidneys as target organs. These effects, based on highly exaggerated pharmacological activity, are comparable to other ACE-inhibitors. No potential for mutagenic or carcinogenic activity and no evidence of reproductive toxicity was apparent for meoxipril. The preclinical data indicate that moexipril possesses a high degree of specifity as an ACE-inhibitor without relevant side effects or gross toxicity.
对新型血管紧张素转换酶(ACE)抑制剂莫昔普利(化学物质登记号82586 - 52 - 5)及其活性二酸代谢物莫昔普利拉的药效学和毒理学特征进行了体内外研究。在体外,莫昔普利拉是豚鼠血清中ACE以及兔肺纯化ACE的强效抑制剂,IC50值分别为2.6和4.9 nmol/L。莫昔普利和莫昔普利拉均浓度依赖性地抑制兔主动脉由血管紧张素I(ANG I)诱导的收缩,而其他药物引起的收缩不受影响,表明这两种化合物对ACE具有高度选择性。在体内实验中也得到了类似结果,分别在口服或静脉给予莫昔普利或莫昔普利拉后,研究清醒的正常血压大鼠和犬对静脉注射ANG I或ANG II的血压升高反应。在大鼠高血压模型以及肾性高血压犬中研究了口服莫昔普利的降压作用。在肾性高血压大鼠中,莫昔普利(0.03 - 10 mg/kg口服)引起血压剂量依赖性降低,阈剂量为0.3 mg/kg。动物每日一次用3 mg/kg/d治疗5天,平均血压降低约70 mmHg,且在实验期间血压维持在该低水平。在自发性高血压大鼠中,口服莫昔普利(30 mg/kg/d)5天导致平均血压从治疗前的180±7 mmHg逐渐降至第4天的谷值127±4 mmHg。在肾周围性高血压犬中,口服莫昔普利(10 mg/kg)联合氢氯噻嗪(10 mg/kg)使平均血压比治疗前对照降低25 mmHg,持续24小时。在所有这些模型中,其作用特点是起效迅速且作用持续时间长。停止治疗后,观察到血压逐渐恢复至基线值。相比之下,在正常血压大鼠中高剂量(100 mg/kg口服)时仅观察到轻微的血压降低作用。还在普遍接受的体外和体内模型中研究了莫昔普利的一般药理学特性。在剂量或浓度比引起ACE抑制的剂量或浓度高100倍以上时,未观察到对中枢神经系统、离体平滑肌制剂、消化系统、肾脏或肺的影响。此外,莫昔普利没有抗炎特性,对血小板功能也无影响。在心血管系统方面,观察到的作用可归因于莫昔普利对ACE的抑制。大鼠和犬的重复剂量毒性研究表明心脏和肾脏是靶器官。基于高度夸大的药理活性,这些作用与其他ACE抑制剂相当。莫昔普利没有致突变或致癌活性的可能性,也没有生殖毒性的证据。临床前数据表明,莫昔普利作为一种ACE抑制剂具有高度特异性,没有相关副作用或严重毒性。