title: Renin inhibitory peptides: a study of structural modifications in the peptide backbone.
abstract: We studied the peptide backbone modifications that improve the metabolic stability of the resulting peptides and yet retain high inhibitory activity against human plasma renin. A systematic investigation of N-alpha-methyl and C-alpha-methyl modifications at the P2 and P3 sites of renin-inhibitory peptides that contain part of the human angiotensinogen sequence led to the discovery of N-alpha-methyl amino acids at the P2 site as a useful structural modification. U-71,038 (11) inhibited human plasma renin with an in vitro potency (IC50) of 2.6 x 10(-10) mol/l. It is highly selective for renin and, as anticipated, resistant to proteolytic degradation. Additional study based on molecular graphic modelling has led us to propose a gamma-lactam conformational constraint at the P2-P3 site. This pseudo-dipeptide has proved useful in the preparation of active renin inhibitors. Compound 18a inhibited human plasma renin with an in vitro potency (IC50) of 2.1 x 10(-9) mol/l. This class of compounds also offers structural features for the study of enzyme-bound conformers.
authors.affiliation: Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
authors.forename: S
authors.initials: S
authors.lastname: Thaisrivongs
authors.forename: D T
authors.initials: DT
authors.lastname: Pals
authors.forename: S R
authors.initials: SR
authors.lastname: Turner
authors.forename: L T
authors.initials: LT
authors.lastname: Kroll
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids; D015195:Drug Design; D006801:Humans; D008745:Methylation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000235:genetics; D000092502:Renin Inhibitors
chemical_list: D000596:Amino Acids; D009842:Oligopeptides; D000092502:Renin Inhibitors; C027509:renin inhibitory peptide