Synthesis of novel inhibitors of the HIV-1 protease: difunctional enols of simple N-protected amino acids.
A series of enol HIV-1 protease inhibitors which show competitive inhibition and the structure-activity relationship study which led to the design of these compounds are reported. By systematically modifying simple amino acids, Boc-Phe enol and Boc-Tyr enol derivatives yield nanomolar Kiapp values (Kiapp = 0.485 microM and Kiapp = 0.425 microM, respectively). These enols are of low molecular weight (< 500 g/mol) and of non-peptidic nature. The enols are synthesized in a one step chemical synthesis and modifications to increase their potency could easily be performed. Boc-Phe enol and Boc-Tyr enol showed low inhibitory effect on pepsin, Kiapps of 23 and 149 microM, respectively, and Boc-Phe enol showed a Kiapp of 20 microM for cathepsin D. Neither of these two compounds inhibited renin (< 10% inhibition at 200 microM).
Vaillancourt
M
M
Institut Armand-Frappier, Université du Québec, Laval, Canada.
Vanasse
B
B
Le Berre
N
N
Cohen
E
E
Sauvé
G
G
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010434:Pepsin A / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000596:Amino Acids; D002402:Cathepsin D; D017320:HIV Protease Inhibitors; D010434:Pepsin A; D000092502:Renin Inhibitors