Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 2.
HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are part of the combination therapy currently used to treat HIV infection. The features of a new NNRTI drug for HIV treatment must include selective potent activity against both wild-type virus as well as against mutant virus that have been selected by use of current antiretroviral treatment regimens. Based on analogy with known HIV-1 NNRTI inhibitors and modeling studies utilizing the X-ray crystal structure of inhibitors bound in the HIV-1 RT, a series of substituted 2-quinolones was synthesized and evaluated as HIV-1 inhibitors.
Freeman
George A
GA
GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA. Andy.A.Freeman@gsk.com
Andrews Iii
C Webster
CW
Hopkins
Andrew L
AL
Lowell
Gina S
GS
Schaller
Lee T
LT
Cowan
Jill R
JR
Gonzales
Stephen S
SS
Koszalka
George W
GW
Hazen
Richard J
RJ
Boone
Lawrence R
LR
Ferris
Rob G
RG
Creech
Katrina L
KL
Roberts
Grace B
GB
Short
Steven A
SA
Weaver
Kurt
K
Reynolds
David J
DJ
Milton
John
J
Ren
Jingshan
J
Stuart
David I
DI
Stammers
David K
DK
Chan
Joseph H
JH
D000480:Alkynes; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D003521:Cyclopropanes; D015195:Drug Design; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010078:Oxazines / Q000737:chemistry; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D015363:Quinolones; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C098320:efavirenz