title: Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1.
abstract: The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC(50)s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.
authors.affiliation: Department of Discovery Biology, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom. romu.corbau@pfizer.com
authors.forename: Romuald
authors.initials: R
authors.lastname: Corbau
authors.forename: Julie
authors.initials: J
authors.lastname: Mori
authors.forename: Chris
authors.initials: C
authors.lastname: Phillips
authors.forename: Lesley
authors.initials: L
authors.lastname: Fishburn
authors.forename: Alex
authors.initials: A
authors.lastname: Martin
authors.forename: Charles
authors.initials: C
authors.lastname: Mowbray
authors.forename: Wendy
authors.initials: W
authors.lastname: Panton
authors.forename: Caroline
authors.initials: C
authors.lastname: Smith-Burchnell
authors.forename: Adele
authors.initials: A
authors.lastname: Thornberry
authors.forename: Heather
authors.initials: H
authors.lastname: Ringrose
authors.forename: Thorsten
authors.initials: T
authors.lastname: Knöchel
authors.forename: Steve
authors.initials: S
authors.lastname: Irving
authors.forename: Mike
authors.initials: M
authors.lastname: Westby
authors.forename: Anthony
authors.initials: A
authors.lastname: Wood
authors.forename: Manos
authors.initials: M
authors.lastname: Perros
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009570:Nitriles; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase