Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers of HIV protease inhibitors
| Autor: | Wim Bert Griet Schepens, Judith Eva Baumeister, Tim H. M. Jonckers, Geerwin Yvonne Paul Haché, Sabine Hallenberger, Marie-Claude Rouan, Jennifer C. Sasaki |
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| Rok vydání: | 2012 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Pharmaceutical Science Biochemistry Structure-Activity Relationship chemistry.chemical_compound Dogs Pharmacokinetics Amide Drug Discovery medicine Animals Cytochrome P-450 CYP3A Humans HIV Protease Inhibitor Benzothiazoles Molecular Biology ADME Benzoxazoles CYP3A4 Organic Chemistry HIV Protease Inhibitors Benzoxazole Amides Rats chemistry Benzothiazole HIV-1 Cytochrome P-450 CYP3A Inhibitors Molecular Medicine Ritonavir Caco-2 Cells Half-Life medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:4998-5002 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2012.06.022 |
| Popis: | A new class of benzoxazole and benzothiazole amide derivatives exhibiting potent CYP3A4 inhibiting properties was identified. Extensive lead optimization was aimed at improving the CYP3A4 inhibitory properties as well as overall ADME profile of these amide derivatives. This led to the identification of thiazol-5-ylmethyl (2S,3R)-4-(2-(ethyl(methyl)amino)-N-isobutylbenzo[d]oxazole-6-carboxamido)-3-hydroxy-1-phenylbutan-2-ylcarbamate (C1) as a lead candidate for this class. This compound together with structurally similar analogues demonstrated excellent ‘boosting’ properties when tested in dogs. These findings warrant further evaluation of their properties in an effort to identify valuable alternatives to Ritonavir as pharmacokinetic enhancers. |
| Databáze: | OpenAIRE |
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