Renin inhibitors. III. Synthesis and structure-activity relationships of transition-state inhibitors containing dihydroxyethylene isostere at the P1-P1 site.
Chem Pharm Bull (Tokyo)
; 42(2): 306-13, 1994 Feb.
Article
em En
| MEDLINE
| ID: mdl-8149456
ABSTRACT
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 P1-P1 site are potent renin inhibitors. (2S,3R,4S)-4-[N-[(2S)-3-Ethylsulfonyl-2-(1-naphthylmethyl)propiony l]-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.
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Base de dados:
MEDLINE
Assunto principal:
Morfolinas
/
Renina
/
Norleucina
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
1994
Tipo de documento:
Article