1,4-Dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: extended exploration on phenyl ring substitutions and preliminary ADME/PK studies.
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.
Tong
Yunsong
Y
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>
Claiborne
Akiyo
A
Pyzytulinska
Magdalena
M
Tao
Zhi-Fu
ZF
Stewart
Kent D
KD
Kovar
Peter
P
Chen
Zehan
Z
Credo
Robert B
RB
Guan
Ran
R
Merta
Philip J
PJ
Zhang
Haiying
H
Bouska
Jennifer
J
Everitt
Elizabeth A
EA
Murry
Bernard P
BP
Hickman
Dean
D
Stratton
Tim J
TJ
Wu
Jian
J
Rosenberg
Saul H
SH
Sham
Hing L
HL
Sowin
Thomas J
TJ
Lin
Nan-horng
NH
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
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