title: Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase.
abstract: A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
authors.affiliation: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. zachary.sweeney@roche.com
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
authors.forename: James P
authors.initials: JP
authors.lastname: Dunn
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Heilek
authors.forename: Pete
authors.initials: P
authors.lastname: Dunten
authors.forename: Todd R
authors.initials: TR
authors.lastname: Elworthy
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Han
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Donald R
authors.initials: DR
authors.lastname: Hirschfeld
authors.forename: J Heather
authors.initials: JH
authors.lastname: Hogg
authors.forename: Walter
authors.initials: W
authors.lastname: Huber
authors.forename: Ann C
authors.initials: AC
authors.lastname: Kaiser
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Kertesz
authors.forename: Woongki
authors.initials: W
authors.lastname: Kim
authors.forename: Taraneh
authors.initials: T
authors.lastname: Mirzadegan
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roepel
authors.forename: Y David
authors.initials: YD
authors.lastname: Saito
authors.forename: Tania M P C
authors.initials: TM
authors.lastname: Silva
authors.forename: Steven
authors.initials: S
authors.lastname: Swallow
authors.forename: Jahari L
authors.initials: JL
authors.lastname: Tracy
authors.forename: Armando
authors.initials: A
authors.lastname: Villasenor
authors.forename: Harit
authors.initials: H
authors.lastname: Vora
authors.forename: Amy S
authors.initials: AS
authors.lastname: Zhou
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
mesh_terms: D000818:Animals; D004285:Dogs; D024882:Drug Resistance, Viral / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D011724:Pyridazines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase