New modified heterocyclic phenylalanine derivatives. Incorporation into potent inhibitors of human renin.
Modified heterocyclic phenylalanine analogues designed as replacements for the P3-P4 region were synthesized and incorporated into renin inhibitors. These inhibitors were found to have significant activity versus human recombinant renin, as well as in vivo activity. The compounds proved to be very resistant to chymotrypsin degradation, as exemplified by compound 8, which remained greater than 60% intact after a 24-h exposure to chymotrypsin. In contrast, the Boc-Phe analogue was nearly completely degraded after 1 h. Compound 6 proved to be the most potent renin inhibitor with an IC50 = 8.9 nM. These stable cyclized phenylalanines should prove to be generally useful as a substitute for Boc-Phe in protease inhibitors.
Ocain
T D
TD
Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Deininger
D D
DD
Russo
R
R
Senko
N A
NA
Katz
A
A
Kitzen
J M
JM
Mitchell
R
R
Oshiro
G
G
Russo
A
A
Stupienski
R
R
D000803:Angiotensin I / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002918:Chymotrypsin / Q000378:metabolism; D004355:Drug Stability; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives*; D012083:Renin / Q000097:blood; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction; D000092502:Renin Inhibitors
D000803:Angiotensin I; D002918:Chymotrypsin; D006571:Heterocyclic Compounds; D007211:Indoles; D010649:Phenylalanine; D012083:Renin; D000092502:Renin Inhibitors; C073518:4-cyclohexyl-2-hydroxy-3-((2-((2-(1-oxo-1,3-dihydroisoindol-2-yl)-3-phenylpropionyl)amino)pentanoyl)amino)butyric acid isopropyl ester