1. Angiotensin converting enzyme inhibitory activity of SCH 33844 (spirapril) in rats, dogs and monkeys
- Author
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E J, Sybertz, T, Baum, H S, Ahn, D M, Desiderio, K K, Pula, R, Tedesco, P, Washington, C, Sabin, E, Smith, and F, Becker
- Subjects
Male ,Chemical Phenomena ,Drug Administration Routes ,Brain ,Angiotensin-Converting Enzyme Inhibitors ,Drug Synergism ,Rats, Inbred Strains ,Peptidyl-Dipeptidase A ,Bradykinin ,Rats ,Chemistry ,Macaca fascicularis ,Dogs ,Enalapril ,Animals ,Female ,Angiotensin I - Abstract
SCH 33844 is a new non-sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of the synthetic substrate hippuryl-histidyl-leucine by rabbit lung ACE in vitro with an IC50 (concentration inhibiting enzyme by 50%) of 0.81 nM. The ester was 83 times less active. Intravenous administration of SCH 33844 and its diacid inhibited pressor responses to angiotensin I (AI) in anesthetized rats with calculated ID50's of 16 and 8 micrograms/kg, respectively. Oral administration of SCH 33844 (0.03-1 mg/kg) inhibited AI pressor responses in conscious rats with a duration of 24 hr at the highest dose. The diacid was inactive. Intravenous administration of SCH 33844 (100-1000 micrograms/kg) or its diacid (30 micrograms/kg) to anesthetized dogs inhibited AI pressor activity and potentiated the depressor response to bradykinin. SCH 33844 inhibited AI responses in conscious dogs following oral administration of 0.3-3 mg/kg. Oral administration of SCH 33844 (1 mg/kg) to conscious monkeys inhibited AI pressor responses for the 4 hr duration of study. In conclusion, SCH 33844 is a potent, orally effective ACE inhibitor in rats, dogs and monkeys.
- Published
- 1987