title: 1,4-Dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: extended exploration on phenyl ring substitutions and preliminary ADME/PK studies.
abstract: A study on substitutions at the four open positions on the phenyl ring of the 1,4-dihydroindeno[1,2-c]pyrazoles as potent CHK-1 inhibitors is described. Bis-substitution at both the 6- and 7-positions led to inhibitors with IC(50) values below 0.3nM. The compound with the best overall activities (36) was able to potentiate the anti-proliferative effect of doxorubicin in HeLa cells by at least 47-fold. Physicochemical, metabolic, and pharmacokinetic properties of selected inhibitors are also disclosed.
authors.affiliation: Cancer Research, Global Pharmaceutical R&D, R47S, AP10, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. yunsong.tong@abbott.com <yunsong.tong@abbott.com>
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Tong
authors.forename: Akiyo
authors.initials: A
authors.lastname: Claiborne
authors.forename: Magdalena
authors.initials: M
authors.lastname: Pyzytulinska
authors.forename: Zhi-Fu
authors.initials: ZF
authors.lastname: Tao
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Robert B
authors.initials: RB
authors.lastname: Credo
authors.forename: Ran
authors.initials: R
authors.lastname: Guan
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Merta
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Everitt
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Murry
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Stratton
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sowin
authors.forename: Nan-horng
authors.initials: NH
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D000071877:Checkpoint Kinase 1; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004249:DNA Damage; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605871:Chek1 protein, rat