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 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.
Sweeney
Zachary K
ZK
Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, USA. zachary.sweeney@roche.com
Harris
Seth F
SF
Arora
Seth F
SF
Javanbakht
Hassan
H
Li
Yu
Y
Fretland
Jennifer
J
Davidson
James P
JP
Billedeau
J Roland
JR
Gleason
Shelley K
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Hirschfeld
Donald
D
Kennedy-Smith
Joshua J
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Mirzadegan
Taraneh
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Roetz
Ralf
R
Smith
Mark
M
Sperry
Sarah
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Suh
Judy M
JM
Wu
Jeffrey
J
Tsing
Stan
S
Villaseñor
Armando G
AG
Paul
Amber
A
Su
Guoping
G
Heilek
Gabrielle
G
Hang
Julie Q
JQ
Zhou
Amy S
AS
Jernelius
Jesper A
JA
Zhang
Fang-Jie
FJ
Klumpp
Klaus
K
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002461:Cell Line, Transformed; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D000882:Haplorhini; D006801:Humans; D006860:Hydrogen Bonding; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase