Discovery of Ritonavir, a Potent Inhibitor of HIV Protease with High Oral Bioavailability and Clinical Efficacy

• Published in: Journal of medicinal chemistry Vol. 41; no. 4; pp. 602 - 617
• Main Authors: Kempf, Dale J, Sham, Hing L, Marsh, Kennan C, Flentge, Charles A, Betebenner, David, Green, Brian E, McDonald, Edith, Vasavanonda, Sudthida, Saldivar, Ayda, Wideburg, Norman E, Kati, Warren M, Ruiz, Lisa, Zhao, Chen, Fino, LynnMarie, Patterson, Jean, Molla, Akhteruzzaman, Plattner, Jacob J, Norbeck, Daniel W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.02.1998; Amer Chemical Soc
• Subjects: Administration, Oral; AIDS/HIV; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Biological Availability; Chemistry, Medicinal; Crystallography, X-Ray; HIV Protease - chemistry; HIV Protease - metabolism; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; Human immunodeficiency virus; Life Sciences & Biomedicine; Medical sciences; Metabolic Clearance Rate; Models, Molecular; Molecular Conformation; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Conformation; Pyridines - chemistry; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; ritonavir; Ritonavir - analogs & derivatives; Ritonavir - chemistry; Ritonavir - pharmacokinetics; Ritonavir - pharmacology; Science & Technology; Solubility; Structure-Activity Relationship; IMMUNODEFICIENCY-VIRUS PROTEASE; C2 SYMMETRICAL INHIBITORS; RETROVIRAL PROTEASES; PHARMACOKINETICS; SPECIFICITY; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; ANTIVIRAL ACTIVITY; DRUG-DESIGN; TYPE-1 PROTEASE; Five membered ring; Enzyme; Ritonavir; Oral administration; Retroviridae; Enzyme inhibitor; Bioavailability; Lentivirus; Organic carbamate; Virus; Peptidases; α-Aminoacid; Structure activity relation; Animal; Six membered ring; Hydrolases; Antiviral; Human immunodeficiency virus; Pharmacokinetics; Chemical synthesis; Heterocyclic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970636+

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 μM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.