title: A novel series of IKKβ inhibitors part I: Initial SAR studies of a HTS hit.
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 early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
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: 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: Juan C
authors.initials: JC
authors.lastname: Jaen
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: Michelle F
authors.initials: MF
authors.lastname: Browner
mesh_terms: D000818:Animals; D004285:Dogs; D005260:Female; D057166:High-Throughput Screening Assays; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011804:Quinolines / Q000737:chemistry; D051381:Rats; D012663:Semicarbazides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011804:Quinolines; D012663:Semicarbazides; C005151:thiosemicarbazide; C037219:quinoline; D051550:I-kappa B Kinase