Cyanopyridyl containing 1,4-dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: improving oral biovailability.
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.
Tong
Yunsong
Y
Cancer Research, Global Pharmaceutical R&D, R47S, AP10, Abbott Laboratories, 100 Abbott Park, Abbott Park, IL 60064, USA. yunsong.tong@abbott.com
Przytulinska
Magdalena
M
Tao
Zhi-Fu
ZF
Bouska
Jennifer
J
Stewart
Kent D
KD
Park
Chang
C
Li
Gaoquan
G
Claiborne
Akiyo
A
Kovar
Peter
P
Chen
Zehan
Z
Merta
Philip J
PJ
Bui
Mai-Ha
MH
Olson
Amanda
A
Osterling
Donald
D
Zhang
Haiying
H
Sham
Hing L
HL
Rosenberg
Saul H
SH
Sowin
Thomas J
TJ
Lin
Nan-Horng
NH
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
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