2,4-disubstituted pyrimidines: a novel class of KDR kinase inhibitors.
2,4-Disubstituted pyrimidines were synthesized as a novel class of KDR kinase inhibitors. Evaluation of the SAR of the screening lead compound 1 (KDR IC(50)=105 nM, Cell IC(50)=8% inhibition at 500 nM) led to the potent 3,5-dimethylaniline derivative 2d (KDR IC(50)=6 nM, cell IC(50)=19 nM).
Departments of Medicinal Chemistry and Cancer Research, Merck Research Laboratories, 19486, West Point, PA, USA
Peter J
PJ
Manley
Adrienne E
AE
Balitza
Mark T
MT
Bilodeau
Kathleen E
KE
Coll
George D
GD
Hartman
Rosemary C
RC
McFall
Keith W
KW
Rickert
Leonard D
LD
Rodman
Kenneth A
KA
Thomas
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D040301:Vascular Endothelial Growth Factor Receptor-2