title: Synthesis and biological activity of some transition-state inhibitors of human renin.
abstract: A series of renin inhibitors containing the dipeptide transition state mimics (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyloctanoic acid (Leu (OH)/Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (CHa /(OH)/Val) was prepared. A structure-activity study with Boc-Phe-His-Leu (OH)/Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha (OH)/ Val- NHC4H9-n (8i) which has the length of a tetrapeptide and contains only one natural amino acid. Compound 8i had an IC50 of 2 x 10(-9) M against human renin and showed high enzyme specificity; IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 x 10(-6) and 3 x 10(-6) M, respectively). In salt-depleted marmosets, 8i inhibited plasma renin activity PRA and lowered blood pressure for up to 2 h after oral administration of a dose of 10 mg/kg.
mesh_terms: D000596:Amino Acids; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002143:Callitrichinae; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D055598:Chemical Phenomena; D002621:Chemistry; D004151:Dipeptides; D004285:Dogs; D006801:Humans; D010434:Pepsin A / Q000037:antagonists & inhibitors; D012083:Renin / Q000097:blood; D013329:Structure-Activity Relationship; D013450:Sulfones; D000092502:Renin Inhibitors
chemical_list: D000596:Amino Acids; D002402:Cathepsin D; D004151:Dipeptides; D010434:Pepsin A; D012083:Renin; D013450:Sulfones; D000092502:Renin Inhibitors