title: Novel indazole non-nucleoside reverse transcriptase inhibitors using molecular hybridization based on crystallographic overlays.
abstract: 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.
authors.affiliation: Discovery Chemistry, Sandwich Laboratories, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom. Lyn.Jones@pfizer.com
authors.forename: Lyn H
authors.initials: LH
authors.lastname: Jones
authors.forename: Gill
authors.initials: G
authors.lastname: Allan
authors.forename: Oscar
authors.initials: O
authors.lastname: Barba
authors.forename: Catherine
authors.initials: C
authors.lastname: Burt
authors.forename: Romuald
authors.initials: R
authors.lastname: Corbau
authors.forename: Thomas
authors.initials: T
authors.lastname: Dupont
authors.forename: Thorsten
authors.initials: T
authors.lastname: Knöchel
authors.forename: Steve
authors.initials: S
authors.lastname: Irving
authors.forename: Donald S
authors.initials: DS
authors.lastname: Middleton
authors.forename: Charles E
authors.initials: CE
authors.lastname: Mowbray
authors.forename: Manos
authors.initials: M
authors.lastname: Perros
authors.forename: Heather
authors.initials: H
authors.lastname: Ringrose
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Swain
authors.forename: Robert
authors.initials: R
authors.lastname: Webster
authors.forename: Mike
authors.initials: M
authors.lastname: Westby
authors.forename: Chris
authors.initials: C
authors.lastname: Phillips
mesh_terms: 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
chemical_list: 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