Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors.
The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC(50)=3.1 nM).
Brnardic
Edward J
EJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. edward_brnardic@merck.com
Garbaccio
Robert M
RM
Fraley
Mark E
ME
Tasber
Edward S
ES
Steen
Justin T
JT
Arrington
Kenneth L
KL
Dudkin
Vadim Y
VY
Hartman
George D
GD
Stirdivant
Steven M
SM
Drakas
Bob A
BA
Rickert
Keith
K
Walsh
Eileen S
ES
Hamilton
Kelly
K
Buser
Carolyn A
CA
Hardwick
James
J
Tao
Weikang
W
Beck
Stephen C
SC
Mao
Xianzhi
X
Lobell
Robert B
RB
Sepp-Lorenzino
Laura
L
Yan
Youwei
Y
Ikuta
Mari
M
Munshi
Sanjeev K
SK
Kuo
Lawrence C
LC
Kreatsoulas
Constantine
C
D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship