Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.
Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.
Huang
Shaei
S
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. shaei_huang@merck.com
Garbaccio
Robert M
RM
Fraley
Mark E
ME
Steen
Justin
J
Kreatsoulas
Constantine
C
Hartman
George
G
Stirdivant
Steve
S
Drakas
Bob
B
Rickert
Keith
K
Walsh
Eileen
E
Hamilton
Kelly
K
Buser
Carolyn A
CA
Hardwick
James
J
Mao
Xianzhi
X
Abrams
Marc
M
Beck
Steve
S
Tao
Weikang
W
Lobell
Rob
R
Sepp-Lorenzino
Laura
L
Yan
Youwei
Y
Ikuta
Mari
M
Murphy
Joan Zugay
JZ
Sardana
Vinod
V
Munshi
Sanjeev
S
Kuo
Lawrence
L
Reilly
Michael
M
Mahan
Elizabeth
E
D000818:Animals; D001665:Binding Sites; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007211:Indoles; D015363:Quinolones; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1