Omega-carboxypyridyl substituted ureas as Raf kinase inhibitors: SAR of the amide substituent.
Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.
Khire
Uday R
UR
Department of Chemistry Research, Bayer Research Center, 400Morgan Lane, West Haven, CT 06516, USA. uday.khire.b@bayer.com
Bankston
Donald
D
Barbosa
James
J
Brittelli
David R
DR
Caringal
Yolanda
Y
Carlson
Robert
R
Dumas
Jacques
J
Gane
Todd
T
Heald
Sarah L
SL
Hibner
Barbara
B
Johnson
Jeffrey S
JS
Katz
Michael E
ME
Kennure
Nancy
N
Kingery-Wood
Jill
J
Lee
Wendy
W
Liu
Xiao-Gao
XG
Lowinger
Timothy B
TB
McAlexander
Ian
I
Monahan
Mary-Katherine
MK
Natero
Reina
R
Renick
Joel
J
Riedl
Bernd
B
Rong
Hong
H
Sibley
Robert N
RN
Smith
Roger A
RA
Wolanin
Donald
D
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D016367:Baculoviridae / Q000235:genetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012995:Solubility; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
D000577:Amides; D004791:Enzyme Inhibitors; D011725:Pyridines; D011994:Recombinant Proteins; D014508:Urea; D019908:Proto-Oncogene Proteins c-raf; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human