title: A novel series of IKKβ inhibitors part II: description of a potent and pharmacologically active series of analogs.
abstract: A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
authors.affiliation: Medicinal Chemistry, Amgen Inc, 1120 Veterans Blvd, South San Francisco, CA 94080, USA. tcushing@amgen.com
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Cushing
authors.forename: Vijay
authors.initials: V
authors.lastname: Baichwal
authors.forename: Karen
authors.initials: K
authors.lastname: Berry
authors.forename: Roland
authors.initials: R
authors.lastname: Billedeau
authors.forename: Viola
authors.initials: V
authors.lastname: Bordunov
authors.forename: Chris
authors.initials: C
authors.lastname: Broka
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Browner
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.forename: David
authors.initials: D
authors.lastname: Clark
authors.forename: Stacie
authors.initials: S
authors.lastname: Dalrymple
authors.forename: Michael
authors.initials: M
authors.lastname: DeGraffenreid
authors.forename: Adrian
authors.initials: A
authors.lastname: Gill
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Hao
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Hawley
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Sharada S
authors.initials: SS
authors.lastname: Labadie
authors.forename: Marc
authors.initials: M
authors.lastname: Labelle
authors.forename: Csaba
authors.initials: C
authors.lastname: Lehel
authors.forename: Pu-Ping
authors.initials: PP
authors.lastname: Lu
authors.forename: Joel
authors.initials: J
authors.lastname: McIntosh
authors.forename: Shichang
authors.initials: S
authors.lastname: Miao
authors.forename: Camran
authors.initials: C
authors.lastname: Parast
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Shin
authors.forename: Eric B
authors.initials: EB
authors.lastname: Sjogren
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Smith
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Talamas
authors.forename: George
authors.initials: G
authors.lastname: Tonn
authors.forename: Keith M
authors.initials: KM
authors.lastname: Walker
authors.forename: Nigel P C
authors.initials: NP
authors.lastname: Walker
authors.forename: Holger
authors.initials: H
authors.lastname: Wesche
authors.forename: Chris
authors.initials: C
authors.lastname: Whitehead
authors.forename: Matt
authors.initials: M
authors.lastname: Wright
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
mesh_terms: D000818:Animals; D004285:Dogs; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D012663:Semicarbazides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D047428:Protein Kinase Inhibitors; D011804:Quinolines; D012663:Semicarbazides; C005151:thiosemicarbazide; C037219:quinoline; D051550:I-kappa B Kinase; D013890:Thiourea