Design of annulated pyrazoles as inhibitors of HIV-1 reverse transcriptase.
J Med Chem
; 51(23): 7449-58, 2008 Dec 11.
Article
em En
| MEDLINE
| ID: mdl-19007201
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Desenho de Fármacos
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Inibidores da Transcriptase Reversa
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Transcriptase Reversa do HIV
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article