title: Design of annulated pyrazoles as inhibitors of HIV-1 reverse transcriptase.
abstract: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class.The binding mode maintains the beta13 and beta14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.
authors.affiliation: Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, USA. zachary.sweeney@roche.com
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Seth F
authors.initials: SF
authors.lastname: Arora
authors.forename: Hassan
authors.initials: H
authors.lastname: Javanbakht
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fretland
authors.forename: James P
authors.initials: JP
authors.lastname: Davidson
authors.forename: J Roland
authors.initials: JR
authors.lastname: Billedeau
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Gleason
authors.forename: Donald
authors.initials: D
authors.lastname: Hirschfeld
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Kennedy-Smith
authors.forename: Taraneh
authors.initials: T
authors.lastname: Mirzadegan
authors.forename: Ralf
authors.initials: R
authors.lastname: Roetz
authors.forename: Mark
authors.initials: M
authors.lastname: Smith
authors.forename: Sarah
authors.initials: S
authors.lastname: Sperry
authors.forename: Judy M
authors.initials: JM
authors.lastname: Suh
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wu
authors.forename: Stan
authors.initials: S
authors.lastname: Tsing
authors.forename: Armando G
authors.initials: AG
authors.lastname: Villaseñor
authors.forename: Amber
authors.initials: A
authors.lastname: Paul
authors.forename: Guoping
authors.initials: G
authors.lastname: Su
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Heilek
authors.forename: Julie Q
authors.initials: JQ
authors.lastname: Hang
authors.forename: Amy S
authors.initials: AS
authors.lastname: Zhou
authors.forename: Jesper A
authors.initials: JA
authors.lastname: Jernelius
authors.forename: Fang-Jie
authors.initials: FJ
authors.lastname: Zhang
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002461:Cell Line, Transformed; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D000882:Haplorhini; D006801:Humans; D006860:Hydrogen Bonding; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase