Renin inhibitors. Improvements in the stability and biological activity of small peptides containing novel Leu-Val replacements.
We have designed a novel class of potent (0.3-7 nM) renin inhibitors which contain a dihydroxyethylene replacement for what is formally the Leu10-Val11 amide bond. Good potency (0.6 nM), water solubility (greater than 10 mg/ml at 37 degrees C), stability toward degradation by chymotrypsin (t1/2 = 820 min), and in vivo activity in a primate model (15% drop in mean arterial pressure in association with complete inhibition of plasma renin activity) are properties which have been incorporated into compound 10, an interesting new agent to be used in the study of hypertension.
Kleinert
H D
HD
Abbott Laboratories, Cardiovascular Research Division, Abbott Park, IL 60064.
Luly
J R
JR
Marcotte
P A
PA
Perun
T J
TJ
Plattner
J J
JJ
Stein
H
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D002918:Chymotrypsin / Q000378:metabolism; D005030:Ethylenes / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008968:Molecular Conformation; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D002918:Chymotrypsin; D005030:Ethylenes; D010455:Peptides; D000092502:Renin Inhibitors