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

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.