DPC 681 and DPC 684: Potent, Selective Inhibitors of Human Immunodeficiency Virus Protease Active against Clinically Relevant Mutant Variants
| Autor: | Sena Garber, Susan Erickson-Viitanen, Susan Jeffrey, Lee T. Bacheler, Beverly C. Cordova, Joanne Saye, George L. Trainor, Pamela Cawood, Greg D. Harris, Janan Jona, Ronald M. Klabe, Robert F. Kaltenbach, Marc Davies, Getman Daniel P, Sharon Diamond, Kelly Logue |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Genotype medicine.medical_treatment Mutant Administration Oral HIV Infections medicine.disease_cause Antiviral Agents Virus Dogs medicine Animals Humans HIV Protease Inhibitor Pharmacology (medical) Pharmacology Sulfonamides Mutation Protease biology Drug Resistance Microbial Blood Proteins HIV Protease Inhibitors Virology Infectious Diseases Nelfinavir Viral replication Enzyme inhibitor Injections Intravenous HIV-1 biology.protein Female Protein Binding medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 45:3021-3028 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.45.11.3021-3028.2001 |
| Popis: | Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC90). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC90s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC50values of 50values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir). |
| Databáze: | OpenAIRE |
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