Novel indazole non-nucleoside reverse transcriptase inhibitors using molecular hybridization based on crystallographic overlays.
A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack of resilience to mutations in the reverse transcriptase (RT) enzyme. Using structural overlays of the known inhibitors efavirenz and capravirine complexed in RT as a starting point, and structure-based drug design techniques, we have created a novel series of indazole NNRTIs that possess excellent metabolic stability and mutant resilience.
Jones
Lyn H
LH
Discovery Chemistry, Sandwich Laboratories, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom. Lyn.Jones@pfizer.com
Allan
Gill
G
Barba
Oscar
O
Burt
Catherine
C
Corbau
Romuald
R
Dupont
Thomas
T
Knöchel
Thorsten
T
Irving
Steve
S
Middleton
Donald S
DS
Mowbray
Charles E
CE
Perros
Manos
M
Ringrose
Heather
H
Swain
Nigel A
NA
Webster
Robert
R
Westby
Mike
M
Phillips
Chris
C
D000480:Alkynes; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003521:Cyclopropanes; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D004355:Drug Stability; D006678:HIV / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000494:pharmacology
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D007093:Imidazoles; D007191:Indazoles; D018894:Reverse Transcriptase Inhibitors; D013457:Sulfur Compounds; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C098320:efavirenz; C433874:capravirine