title: Cyanopyridyl containing 1,4-dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: improving oral biovailability.
abstract: A series of 1,4-dihydroindeno[1,2-c]pyrazole compounds with a cyanopyridine moiety at the 3-position of the tricyclic pyrazole core was explored as potent CHK-1 inhibitors. The impact of substitutions at the 6 and/or 7-position of the core on pharmacokinetic properties was studied in detail. Compounds carrying a side chain with an ether linker at the 7-position and a terminal morpholino group, such as 29 and 30, exhibited much-improved oral biovailability in mice as compared to earlier generation inhibitors. These compounds also possessed desirable cellular activity in potentiating doxorubicin and will serve as valuable tool compounds for in vivo evaluation of CHK-1 inhibitors to sensitize DNA-damaging agents.
authors.affiliation: Cancer Research, Global Pharmaceutical R&D, R47S, AP10, Abbott Laboratories, 100 Abbott Park, Abbott Park, IL 60064, USA. yunsong.tong@abbott.com
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Tong
authors.forename: Magdalena
authors.initials: M
authors.lastname: Przytulinska
authors.forename: Zhi-Fu
authors.initials: ZF
authors.lastname: Tao
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.forename: Gaoquan
authors.initials: G
authors.lastname: Li
authors.forename: Akiyo
authors.initials: A
authors.lastname: Claiborne
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Merta
authors.forename: Mai-Ha
authors.initials: MH
authors.lastname: Bui
authors.forename: Amanda
authors.initials: A
authors.lastname: Olson
authors.forename: Donald
authors.initials: D
authors.lastname: Osterling
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sowin
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000071877:Checkpoint Kinase 1; D003486:Cyanides / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry*; D007192:Indenes / Q000737:chemistry; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D003486:Cyanides; D007192:Indenes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C031280:pyrazole; C093581:indene; D006859:Hydrogen; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605871:Chek1 protein, rat; C023666:pyridine