Design of Annulated Pyrazoles as Inhibitors of HIV-1 Reverse Transcriptase
| Autor: | Jennifer Fretland, Jeffrey Wu, Nidhi Arora, Fang‐Jie Zhang, Julie Q. Hang, Judy M. Suh, Stan Tsing, Seth F. Harris, Joshua Kennedy-Smith, Amber Paul, James Edward Paul Davidson, Sarah Sperry, J. Roland Billedeau, Mark D. Smith, Gabrielle Heilek, Klaus Klumpp, Guoping Su, Zachary Kevin Sweeney, Hassan Javanbakht, Amy S. Zhou, Taraneh Mirzadegan, Shelley K. Gleason, Yu Li, Ralf Roetz, Jesper A. Jernelius, Donald Roy Hirschfeld, Armando G. Villaseñor |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Anti-HIV Agents Etravirine Microbial Sensitivity Tests Gene mutation Crystallography X-Ray Virus Structure-Activity Relationship Dogs Drug Discovery medicine Animals Humans Cell Line Transformed Binding Sites Molecular Structure biology Reverse-transcriptase inhibitor Chemistry virus diseases Hydrogen Bonding Stereoisomerism Haplorhini biology.organism_classification Virology HIV Reverse Transcriptase Reverse transcriptase Rats Discovery and development of non-nucleoside reverse-transcriptase inhibitors Viral replication Drug Design Lentivirus HIV-1 Pyrazoles Reverse Transcriptase Inhibitors Molecular Medicine medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 51:7449-7458 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm800527x |
| Popis: | Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class.The binding mode maintains the beta13 and beta14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture. |
| Databáze: | OpenAIRE |
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