RENIN INHIBITORS .3. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF TRANSITION-SITE INHIBITORS CONTAINING DIHYDROXYETHYLENE ISOSTERE AT THE P-1-P-1' SITE

被引:0
作者
ATSUUMI, S
FUNABASHI, H
NAKANO, M
KOIKE, Y
TANAKA, S
HARADA, J
MATSUYAMA, K
IKENAGA, T
MORISHIMA, H
机构
[1] BANYU PHARMACEUT CO LTD, TSUKUBA RES INST, BIOCHEM LABS, TSUKUBA, IBARAKI 30033, JAPAN
[2] BANYU PHARMACEUT CO LTD, TSUKUBA RES INST, NEW DRUG DISCOVERY RES LABS, TSUKUBA, IBARAKI 30033, JAPAN
关键词
RENIN INHIBITOR; ANTIHYPERTENSIVE AGENT; DIHYDROXYETHYLENE ISOSTERE; STRUCTURE-ACTIVITY RELATIONSHIP;
D O I
暂无
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The design, synthesis and structure-activity relationships of transition-state inhibitors containing the dihydroxyethylene isostere at the scissile site are described. The compounds with (2S,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol at the P-1-P-1. site are potent renin inhibitors. (2S,3R,4S)-4-[N-C(2S)-3-Ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-L-norleucyl]amino-5-cyclohexyl-1-morpholino-2,3-pentanediol (2) (BW-175), which is the most potent inhibitor (IC50: 3.3 nM against human renin) in this series, poorly inhibits cathepsin D (IC50: 26000 nM) and pepsin (IC50: > 100000 nM), and thus it is specific for renin. Compound 2 contains only one amino acid and showed an oral bioavailability of 2.8% at 10 mg/kg and 9.7% at 30 mg/kg in rats. The interaction between renin and inhibitor 2 is discussed on the basis of molecular modeling studies.
引用
收藏
页码:306 / 313
页数:8
相关论文
共 37 条
[31]   DESIGN OF A WELL-ABSORBED RENIN INHIBITOR [J].
ROSENBERG, SH ;
KLEINERT, HD ;
STEIN, HH ;
MARTIN, DL ;
CHEKAL, MA ;
COHEN, J ;
EGAN, DA ;
TRICARICO, KA ;
BAKER, WR .
JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (01) :469-471
[32]   DESIGN AND SYNTHESIS OF POTENT AND SPECIFIC RENIN INHIBITORS CONTAINING DIFLUOROSTATINE, DIFLUOROSTATONE, AND RELATED ANALOGS [J].
THAISRIVONGS, S ;
PALS, DT ;
KATI, WM ;
TURNER, SR ;
THOMASCO, LM ;
WATT, W .
JOURNAL OF MEDICINAL CHEMISTRY, 1986, 29 (10) :2080-2087
[33]   RENIN INHIBITORS - DESIGN OF ANGIOTENSINOGEN TRANSITION-STATE ANALOGS CONTAINING NOVEL (2R,3R,4R,5S)-5-AMINO-3,4-DIHYDROXY-2-ISOPROPYL-7-METHYLOCTANOIC ACID [J].
THAISRIVONGS, S ;
PALS, DT ;
KROLL, LT ;
TURNER, SR ;
HAN, FS .
JOURNAL OF MEDICINAL CHEMISTRY, 1987, 30 (06) :976-982
[34]  
THAISRIVONGS S, 1985, J MED CHEM, V28, P1555
[35]  
TOBE H, 1979, AGR BIOL CHEM TOKYO, V43, P591, DOI 10.1080/00021369.1979.10863474
[36]   DESIGN AND SYNTHESIS OF P2-P1'-LINKED MACROCYCLIC HUMAN RENIN INHIBITORS [J].
WEBER, AE ;
HALGREN, TA ;
DOYLE, JJ ;
LYNCH, RJ ;
SIEGL, PKS ;
PARSONS, WH ;
GREENLEE, WJ ;
PATCHETT, AA .
JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (09) :2692-2701
[37]  
ZAPATERO CA, 1991, ADV EXP MED BIOL, V306, P9