Pharmacological and toxicological studies of the new angiotensin converting enzyme inhibitor moexipril hydrochloride.
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.
Friehe
H
H
Department of Pharmacology and Toxicology, Schwarz Pharma AG, Monheim, Germany.
Ney
P
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011247:Pregnancy; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007546:Isoquinolines; D011355:Prodrugs; D044005:Tetrahydroisoquinolines; C058302:moexipril