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...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 51; no. 23
Main Authors:	Sweeney, Z.K., Harris, S.F., Arora, N., Javanbakht, H., Li, Y., Fretland, J., Davidson, J.P., Billedeau, J.R., Gleason, S., Hirschfeld, D., Kennedy-Smith, J.J., Mirzadegan, T., Roetz, R., Smith, M., Sperry, S., Suh, J.M., Wu, J., Tsing, S., Villasenor, A.G., Paul, A., Su, G.
Format:	Journal Article
Language:	English
Published:	United States 26-05-2009
Subjects:	AIDS VIRUS BASIC BIOLOGICAL SCIENCES CELL CULTURES DISTRIBUTION ENZYME INHIBITORS ENZYMES ETHERS GENE MUTATIONS GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE HUMAN POPULATIONS INTERACTIONS NITRILES NUCLEOTIDYLTRANSFERASES OPTIMIZATION ORGANIC CHLORINE COMPOUNDS ORGANIC FLUORINE COMPOUNDS Other,OTHER, CHEM, MEDAPPS PYRAZOLES STRAINS STRUCTURE-ACTIVITY RELATIONSHIPS THERAPEUTIC USES TRANSFERASES VOLUME
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Summary:	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.
Bibliography:	SLAC-REPRINT-2009-302 USDOE AC02-76SF00515
ISSN:	0022-2623 1520-4804