Antihypertensive and natriuretic effects of CGS 30440, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase 24.11.
Dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitors, by decreasing angiotensin-II production and by preventing the degradation of atrial natriuretic peptide (ANP), may be useful for the treatment of hypertension and congestive heart failure. The thiol dipeptide CGS 30440 (prodrug of CGS 30008, IC50: ACE/NEP = 19/2 nM) administered to rats (10 mg/kg p.o.) inhibited lung tissue ACE activity by 98% and 61% at 1 and 24 hr (P < .001) and inhibited the angiotensin-I pressor response by 75 to 90% for more than 6 hr. Renal tissue NEP activity was reduced by 80% at 1 hr and 73% at 24 hr (P < .001). In rats supplemented with exogenous ANP, CGS 30440 (1 mg/kg p.o.) elevated the concentration of circulating ANP (133%, P < .025) for 4 hr and increased the excretion of urine (300%, P < .001), sodium (194%, P < .025) and cyclic GMP (238%, P < .005). CGS 30440 (10 mg/kg p.o.) administered to hypertensive rats with aortic ligation between the renal arteries (mean arterial blood pressure, 209 +/- 4 mm Hg) produced a 48 mm Hg blood pressure reduction (P < .001) within 4 hr. CGS 30440 given to cynomolgus monkeys at 2 mg/kg inhibited plasma ACE activity by 96% within 1 hr (P < .001), and this inhibition was maintained for 7 and 21 days in monkeys receiving the compound orally at 2.5 mg/kg b.i.d. These studies demonstrate that CGS 30440 is an orally active agent which produces tissue ACE and NEP inhibition in rats and plasma ACE inhibition in primates and suggest that the compound may be useful in the treatment of hypertension and congestive heart failure.
Chatelain
R E
RE
Novartis Pharmaceuticals Corporation, Summit, New Jersey, USA.
Ghai
R D
RD
Trapani
A J
AJ
Odorico
L M
LM
Dardik
B N
BN
De Lombaert
S
S
Lappe
R W
RW
Fink
C A
CA
D000803:Angiotensin I / Q000037:antagonists & inhibitors; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; C100918:N-((1-((2-(acetylthio)-3-methyl-1-oxobutyl)amino)-1-cyclopentyl)carbonyl)-O-methyl-L-tyrosine ethyl ester; D014443:Tyrosine; D009320:Atrial Natriuretic Factor; D000803:Angiotensin I; D015260:Neprilysin