Conformationally constrained renin inhibitory peptides: gamma-lactam-bridged dipeptide isostere as conformational restriction.
A model of the conformation of the enzyme-bound inhibitor of human renin suggested the possibility of a gamma-lactam conformational restriction at the P2-P3 site. Synthetic routes to these gamma-lactam dipeptide isosteres and their incorporation into potential renin inhibitors are described. Peptide VIa,b with a gamma-lactam conformational constraint and a hydroxyethylene isostere at the cleavage site inhibited human plasma renin with an IC50 value of 6.5 nM. The flexibility of these syntheses should make available a number of potential enzyme inhibitors with this structural feature for the study of enzyme-bound conformers.
Thaisrivongs
S
S
Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Pals
D T
DT
Turner
S R
SR
Kroll
L T
LT
D000808:Angiotensinogen; D055598:Chemical Phenomena; D002621:Chemistry; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000808:Angiotensinogen; D004151:Dipeptides; D007769:Lactams; D000092502:Renin Inhibitors