Design of HIV-1 Protease Inhibitors Active on Multidrug-Resistant Virus
| Autor: | Dominique Louis Nestor Ghislain Surleraux, Anik Peeters, Sandra De Meyer, Rudi Wilfried Jan Pauwels, Moses Prabu-Jeyabalan, Piet Wigerinck, Celia A. Schiffer, Geert M. E. Pille, Hilde Azijn, Louis J. R. Maes, Herman Augustinus De Kock, Sandrine Marie Helene Vendeville, Wim Gaston Verschueren, Marie-Pierre de Béthune, Nancy M. King |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Molecular model medicine.medical_treatment Calorimetry In Vitro Techniques Crystallography X-Ray Virus Cell Line Dogs Drug Resistance Multiple Viral Drug Stability HIV-1 protease Drug Discovery medicine Animals Humans Protease inhibitor (pharmacology) Rats Wistar chemistry.chemical_classification Benzoxazoles Sulfonamides Binding Sites Protease biology HIV Protease Inhibitors Rats Multiple drug resistance Thiazoles Enzyme Biochemistry chemistry Enzyme inhibitor HIV-1 Microsomes Liver biology.protein Thermodynamics Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm049454n |
| Popis: | On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile resulting from the extension into the P2' pocket of the HIV-1 protease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|