Design of Annulated Pyrazoles As Inhibitors of HIV-1 Reverse Transcriptase
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 {beta}13 and {beta}14 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.
- Research Organization:
- Stanford Linear Accelerator Center (SLAC)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC02-76SF00515
- OSTI ID:
- 953581
- Report Number(s):
- SLAC-REPRINT-2009-302
- Journal Information:
- J. Med. Chem 51:7449,2008, Journal Name: J. Med. Chem 51:7449,2008 Journal Issue: 23 Vol. 51; ISSN JMCMAR; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- English
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ENZYME INHIBITORS
ENZYMES
ETHERS
GENE MUTATIONS
HUMAN POPULATIONS
INTERACTIONS
NITRILES
NUCLEOTIDYLTRANSFERASES
OPTIMIZATION
ORGANIC CHLORINE COMPOUNDS
ORGANIC FLUORINE COMPOUNDS
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STRUCTURE-ACTIVITY RELATIONSHIPS
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