Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450
| Autor: | Hodge Carl Nicholas, M. J. Otto, Sena Garber, Dean L. Winslow, Grubb M, L. Shum, Korant B, Patrick Y.S. Lam, J. L. Meek, P. E. Aldrich, Charles J. Eyermann, Lee T. Bacheler, M. M. Rayner, T. R. Sharpe, Prabhakar K. Jadhav, C.-H. Chang, Susan Erickson-Viitanen, Carol Reid, David A. Jackson, Maurin Mb |
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| Jazyk: | angličtina |
| Předmět: |
medicine.medical_treatment
Mutant Clinical Biochemistry Administration Oral Crystallography X-Ray Virus Replication Biochemistry Mice Pharmacokinetics HIV-1 protease In vivo Drug Discovery HIV protease medicine HIV Protease Inhibitor Potency Animals Humans Urea Infusions Intravenous Molecular Biology Pharmacology Protease biology Chemistry Drug Resistance Microbial General Medicine Azepines HIV Protease Inhibitors antiviral Bioavailability AIDS Microscopy Electron Solubility biology.protein HIV-1 Molecular Medicine structure-based drug design cyclic urea |
| Zdroj: | Chemistry & Biology. (4):301-314 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/S1074-5521(96)90110-6 |
| Popis: | Background: Effective HIV protease inhibitors must combine potency towards wild-type and mutant variants of HIV with oral bioavailability such that drug levels in relevant tissues continuously exceed that required for inhibition of virus replication. Computer-aided design led to the discovery of cyclic urea inhibitors of the HIV protease. We set out to improve the physical properties and oral bioavailability of these compounds. Results: We have synthesized DMP 450 (bis-methanesulfonic acid salt), a water-soluble cyclic urea compound and a potent inhibitor of HIV replication in cell culture that also inhibits variants of HIV with single amino acid substitutions in the protease. DMP 450 is highly selective for HIV protease, consistent with displacement of the retrovirus-specific structural water molecule. Single doses of 10 mg kg −1 DMP 450 result in plasma levels in man in excess of that required to inhibit wild-type and several mutant HIVs. A plasmid-based, in vivo assay model suggests that maintenance of plasma levels of DMP 450 near the antiviral IC 90 suppresses HIV protease activity in the animal. We did identify mutants that are resistant to DMP 450, however; multiple mutations within the protease gene caused a significant reduction in the antiviral response. Conclusions: DMP 450 is a significant advance within the cyclic urea class of HIV protease inhibitors due to its exceptional oral bioavailability. The data presented here suggest that an optimal cyclic urea will provide clinical benefit in treating AIDS if it combines favorable pharmacokinetics with potent activity against not only single mutants of HIV, but also multiply-mutant variants. |
| Databáze: | OpenAIRE |
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