Preclinical pharmacology of zofenopril, an inhibitor of angiotensin I converting enzyme.
Zofenopril calcium (one-half calcium salt) is a prodrug ester analog of captopril whose biological effects are manifested by its active component, SQ 26,333. Because of the relative insolubilities of both zofenopril calcium and SQ 26,333, zofenopril potassium salt and SQ 26,703, the arginine salt of the active ACE (angiotensin I converting enzyme) inhibitory moiety of zofenopril, were employed in many of the following studies. The in vitro and in vivo pharmacological effects of zofenopril have been evaluated and comparisons have been made to captopril. In vitro, SQ 26,703 was more potent than captopril as an inhibitor of rabbit lung ACE (IC50 = 8 vs. 23 nM). SQ 26,703 was also a potent inhibitor of angiotensin I (AI)-induced contractions (EC50 = 3 nM) and a potentiator of bradykinin-induced contractions (EC50 = 1 nM) of isolated guinea pig ileum, while it had no effect on the inotropic effects of angiotensin II, BaCl2, PGE1, histamine, serotonin, or acetycholine in the same tissue, signifying that zofenopril is a specific inhibitor of ACE. In vivo, the potency of SQ 26,703 was equal to or greater than that of captopril as an inhibitor of an AI pressor response when given intravenously to rats, dogs, and monkeys. After oral administration of equimolar doses, zofenopril was the more effective and longer lasting ACE inhibitor in all three species. In SHR, doses of 6.6 and 22.0 mg/kg, p.o. lowered pressure by 20 and 33 mm Hg, respectively, while 30 mg/kg of captopril lowered pressure by 25 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)
DeForrest
J M
JM
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Waldron
T L
TL
Krapcho
J
J
Turk
C
C
Rubin
B
B
Powell
J R
JR
Cushman
D W
DW
Petrillo
E W
EW
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D005260:Female; D007082:Ileum; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats
D000806:Angiotensin-Converting Enzyme Inhibitors; C044958:zofenopril; D002216:Captopril