Document Detail

Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy.
MedLine Citation:
PMID:  9484509     Owner:  NLM     Status:  MEDLINE    
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.
D J Kempf; H L Sham; K C Marsh; C A Flentge; D Betebenner; B E Green; E McDonald; S Vasavanonda; A Saldivar; N E Wideburg; W M Kati; L Ruiz; C Zhao; L Fino; J Patterson; A Molla; J J Plattner; D W Norbeck
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  41     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1998 Feb 
Date Detail:
Created Date:  1998-03-17     Completed Date:  1998-03-17     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  602-17     Citation Subset:  IM; X    
Pharmaceutical Products Division, Abbott Laboratory, Abbott Park, Illinois 60064, USA.
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MeSH Terms
Administration, Oral
Biological Availability
Crystallography, X-Ray
HIV Protease / chemistry,  metabolism*
HIV Protease Inhibitors / chemistry*,  pharmacokinetics,  pharmacology
Metabolic Clearance Rate
Models, Molecular
Molecular Conformation
Molecular Structure
Protein Conformation
Pyridines / chemistry,  pharmacokinetics,  pharmacology
Recombinant Proteins / antagonists & inhibitors,  chemistry
Ritonavir / analogs & derivatives*,  chemistry*,  pharmacokinetics,  pharmacology
Structure-Activity Relationship
Reg. No./Substance:
0/A 80987; 0/HIV Protease Inhibitors; 0/Pyridines; 0/Recombinant Proteins; 0/Ritonavir; EC 3.4.23.-/HIV Protease

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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