title: Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy.
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.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratory, Abbott Park, Illinois 60064, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: H L
authors.initials: HL
authors.lastname: Sham
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: C A
authors.initials: CA
authors.lastname: Flentge
authors.forename: D
authors.initials: D
authors.lastname: Betebenner
authors.forename: B E
authors.initials: BE
authors.lastname: Green
authors.forename: E
authors.initials: E
authors.lastname: McDonald
authors.forename: S
authors.initials: S
authors.lastname: Vasavanonda
authors.forename: A
authors.initials: A
authors.lastname: Saldivar
authors.forename: N E
authors.initials: NE
authors.lastname: Wideburg
authors.forename: W M
authors.initials: WM
authors.lastname: Kati
authors.forename: L
authors.initials: L
authors.lastname: Ruiz
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.forename: L
authors.initials: L
authors.lastname: Fino
authors.forename: J
authors.initials: J
authors.lastname: Patterson
authors.forename: A
authors.initials: A
authors.lastname: Molla
authors.forename: J J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: D W
authors.initials: DW
authors.lastname: Norbeck
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D019438:Ritonavir / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D011725:Pyridines; D011994:Recombinant Proteins; C092970:A 80987; D016333:HIV Protease; D019438:Ritonavir