ABSTRACT
The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 microM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease/metabolism , Ritonavir/analogs & derivatives , Ritonavir/chemistry , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , HIV Protease/chemistry , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/pharmacology , Metabolic Clearance Rate , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Conformation , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Ritonavir/pharmacokinetics , Ritonavir/pharmacology , Solubility , Structure-Activity RelationshipABSTRACT
Examination of the structural basis for antiviral activity, oral pharmacokinetics, and hepatic metabolism among a series of symmetry-based inhibitors of the human immunodeficiency virus (HIV) protease led to the discovery of ABT-538, a promising experimental drug for the therapeutic intervention in acquired immunodeficiency syndrome (AIDS). ABT-538 exhibited potent in vitro activity against laboratory and clinical strains of HIV-1 [50% effective concentration (EC50) = 0.022-0.13 microM] and HIV-2 (EC50 = 0.16 microM). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC50 for > 12 h. In human trials, a single 400-mg dose of ABT-538 displayed a prolonged absorption profile and achieved a peak plasma concentration in excess of 5 micrograms/ml. These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease.
Subject(s)
Antiviral Agents/pharmacokinetics , HIV Protease Inhibitors/pharmacokinetics , Thiazoles/pharmacokinetics , Valine/analogs & derivatives , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Bile/metabolism , Bile Ducts/physiology , Binding Sites , Biological Availability , Capsules , Female , HIV Protease/chemistry , HIV Protease Inhibitors/administration & dosage , HIV-1/drug effects , HIV-2/drug effects , Humans , Injections, Intravenous , Macaca fascicularis , Male , Metabolic Clearance Rate , Models, Molecular , Molecular Structure , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Ritonavir , Tablets , Thiazoles/administration & dosage , Thiazoles/pharmacology , Tissue Distribution , Valine/administration & dosage , Valine/pharmacokinetics , Valine/pharmacologyABSTRACT
Fluorescence polarization immunoassay of 5-hydroxy-3-indoleacetic acid in urine is described and compared with liquid chromatography (electrochemical detection) and colorimetry. Reports of in-house performance data and results of clinical trials are included to emphasize the usefulness of the assay for routine work.
