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

• Published in: Journal of medicinal chemistry Vol. 31; no. 9; pp. 1839 - 1846
• Main Authors: Buehlmayer, Peter, Caselli, Anthony, Fuhrer, Walter, Goeschke, Richard, Rasetti, Vittorio, Rueger, Heinrich, Stanton, James L, Criscione, Leoluca, Wood, Jeanette M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.09.1988
• Subjects: Amino Acids; Animals; Blood Pressure - drug effects; Callitrichinae; Cathepsin D - antagonists & inhibitors; Chemical Phenomena; Chemistry; Dipeptides; Dogs; Exact sciences and technology; Humans; man; Organic chemistry; Pepsin A - antagonists & inhibitors; Peptides; Preparations and properties; Renin - antagonists & inhibitors; Renin - blood; Structure-Activity Relationship; Sulfones; Enzyme inhibitor; Biological activity; Renin
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00117a027

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.