title: Indole RSK inhibitors. Part 1: discovery and initial SAR.
abstract: A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were identified through high throughput screening. An RSK crystal structure and exploratory SAR were used to define the series pharmacophore. Compounds with good cell potency, such as compounds 43, 44, and 55 were identified, and form the basis for subsequent kinase selectivity optimization.
authors.affiliation: Department of Medicinal Chemistry, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, United States. stephen.boyer.b@gmail.com
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Boyer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Burke
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kirrane
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Snow
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chris
authors.initials: C
authors.lastname: Sarko
authors.forename: Lida
authors.initials: L
authors.lastname: Soleymanzadeh
authors.forename: Alan
authors.initials: A
authors.lastname: Swinamer
authors.forename: John
authors.initials: J
authors.lastname: Westbrook
authors.forename: Frank
authors.initials: F
authors.lastname: Dicapua
authors.forename: Anil
authors.initials: A
authors.lastname: Padyana
authors.forename: Derek
authors.initials: D
authors.lastname: Cogan
authors.forename: Amy
authors.initials: A
authors.lastname: Gao
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Xiong
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Madwed
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashem
authors.forename: Stanley
authors.initials: S
authors.lastname: Kugler
authors.forename: Margaret M
authors.initials: MM
authors.lastname: O'Neill
mesh_terms: D000577:Amides / Q000737:chemistry; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D009584:Nitrogen / Q000737:chemistry; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C573896:1-oxo-2,3,4,5-tetrahydro-1H-(1,4)diazepino(1,2-a)indole-8-carboxamide; D000577:Amides; D001381:Azepines; D004791:Enzyme Inhibitors; D007211:Indoles; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D009584:Nitrogen