Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1
| Autor: | Ronald M. Klabe, James D. Rodgers, Jo Anne Saye, Susan Jeffrey, Sharon Diamond, Jeffrey W. Corbett, Paul Anderson, Chii-Ming Lai, Soo S. Ko, Susan Erickson-Viitanen, Lee T. Bacheler, George L. Trainor, Shelley R. Rabel, Stephen P. Adams |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Pan troglodytes Anti-HIV Agents Mutant Plasma protein binding Biology medicine.disease_cause Antiviral Agents Virus medicine Animals Humans Potency Pharmacology (medical) reproductive and urinary physiology Pharmacology Mutation Stereoisomerism Blood Proteins Nucleotidyltransferase biology.organism_classification Macaca mulatta Virology HIV Reverse Transcriptase Reverse transcriptase Infectious Diseases Amino Acid Substitution embryonic structures Lentivirus HIV-1 Reverse Transcriptase Inhibitors Half-Life Protein Binding |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 43:2893-2897 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3,4-dihydro-2(1 H )quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3,4-dihydro-2(1 H )quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug. |
| Databáze: | OpenAIRE |
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