title: Synthesis of novel inhibitors of the HIV-1 protease: difunctional enols of simple N-protected amino acids.
abstract: 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).
authors.affiliation: Institut Armand-Frappier, Université du Québec, Laval, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Vaillancourt
authors.forename: B
authors.initials: B
authors.lastname: Vanasse
authors.forename: N
authors.initials: N
authors.lastname: Le Berre
authors.forename: E
authors.initials: E
authors.lastname: Cohen
authors.forename: G
authors.initials: G
authors.lastname: Sauvé
mesh_terms: 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
chemical_list: D000596:Amino Acids; D002402:Cathepsin D; D017320:HIV Protease Inhibitors; D010434:Pepsin A; D000092502:Renin Inhibitors