A prodrug approach to the design of cRaf1 kinase inhibitors with improved cellular activity.
Earlier we reported potent cRaf1 kinase inhibitors with a key acidic phenol pharmacophore that had, at best, adequate cellular efficacy. To improve the cellular potency, phenol isosteres and prodrugs were investigated. Many phenol isosteres were synthesized and tested, but failed to provide adequate enzyme potency. A prodrug approach resulted in a 2- to 17-fold improvement over the parent compound in cell-based efficacy.
Wood
E
E
GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Crosby
R M
RM
Dickerson
S
S
Frye
S V
SV
Griffin
R
R
Hunter
R
R
Jung
D K
DK
McDonald
O B
OB
McNutt
R
R
Mahony
W B
WB
Peel
M R
MR
Ray
J
J
Lackey
K
K
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D010636:Phenols / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs; D011506:Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D013329:Structure-Activity Relationship; D048008:TNF Receptor-Associated Factor 3
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010636:Phenols; D011355:Prodrugs; D011506:Proteins; D048008:TNF Receptor-Associated Factor 3; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases