title: Statine-containing dipeptide and tripeptide inhibitors of human renin.
abstract: Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(1-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-methylbutylamide was found to be a highly potent inhibitor of human renin with a Ki value of 1.7 X 10(-9) M. Dipeptide derivatives with the BNMA group at the N-terminal (BNMA-Val-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 10(-5) M. The other derivatives showed detectable inhibition of cathepsin D (IC50, 10(-6) - 10(-7) M) and pepsin (10(-5) - 10(-6) M). All the compounds had little or no effect on trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10(-5) M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity.
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D004151:Dipeptides / Q000494:pharmacology*; D004285:Dogs; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D010434:Pepsin A / Q000037:antagonists & inhibitors; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013552:Swine; D000092502:Renin Inhibitors
chemical_list: D000596:Amino Acids; D002402:Cathepsin D; D004151:Dipeptides; D009842:Oligopeptides; D010434:Pepsin A; D000092502:Renin Inhibitors; C013165:statine