NEW MODIFIED HETEROCYCLIC PHENYLALANINE DERIVATIVES - INCORPORATION INTO POTENT INHIBITORS OF HUMAN RENIN

被引:4
作者
OCAIN, TD
DEININGER, DD
RUSSO, R
SENKO, NA
KATZ, A
KITZEN, JM
MITCHELL, R
OSHIRO, G
RUSSO, A
STUPIENSKI, R
MCCAULLY, RJ
机构
[1] Wyeth-Ayerst Research, New Jersey 08543-8000, CN 8000, Princeton
关键词
D O I
10.1021/jm00083a005
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:823 / 832
页数:10
相关论文
共 28 条
[1]   STRUCTURE AND MECHANISM OF CHYMOTRYPSIN [J].
BLOW, DM .
ACCOUNTS OF CHEMICAL RESEARCH, 1976, 9 (04) :145-152
[2]   NOVEL RENIN INHIBITORS CONTAINING THE AMINO-ACID STATINE [J].
BOGER, J ;
LOHR, NS ;
ULM, EH ;
POE, M ;
BLAINE, EH ;
FANELLI, GM ;
LIN, TY ;
PAYNE, LS ;
SCHORN, TW ;
LAMONT, BI ;
VASSIL, TC ;
STABILITO, II ;
VEBER, DF ;
RICH, DH ;
BOPARI, AS .
NATURE, 1983, 303 (5912) :81-84
[3]  
CAZAUBON C, 1986, J HYPERTENS, V4, pS459
[4]  
GOEL OP, 1988, ORG SYNTH, V67, P69
[6]   RENIN INHIBITORS [J].
GREENLEE, WJ .
PHARMACEUTICAL RESEARCH, 1987, 4 (05) :364-374
[7]   RENIN INHIBITORS [J].
HABER, E .
HYPERTENSION, 1986, 8 (12) :1093-1095
[8]  
HAMADA Y, 1982, CHEM PHARM BULL, V30, P1921
[9]  
HANSON GJ, 1990, BIOCHEM BIOPH RES CO, V160, P1
[10]   A PRACTICAL SYNTHESIS OF AN ORALLY POTENT RENIN INHIBITOR, ISOPROPYL (2R,3S)-4-CYCLOHEXYL-2-HYDROXY-3-(N-[(2R)-2-MORPHOLINOCARBONYLMETHYL-3-(1-NAPHTHYL)PROPIONYL]-L-HISTIDYL)AMINOBUTYRATE [J].
HARADA, H ;
IYOBE, A ;
TSUBAKI, A ;
YAMAGUCHI, T ;
HIRATA, K ;
KAMIJO, T ;
IIZUKA, K ;
KISO, Y .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1990, (09) :2497-2500