Synthesis and biological activity of some transition-state inhibitors of human renin

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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.sbd.Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (Cha.sbd.Val) was prepared. A structure-activity study with Boc-Phe-His-Leu.sbd.Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha.sbd.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 .times. 10-9 M against human renin and showed high enzyme specificity, IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 .times. 10-6 and 3 .times. 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.