2-Hydroxy-4,6-diamino-[1,3,5]triazines: a novel class of VEGF-R2 (KDR) tyrosine kinase inhibitors.
2-Hydroxy-4,6-diamino-[1,3,5]triazines are described which are a novel class of potent inhibitors of the VEGF-R2 (flk-1/KDR) tyrosine kinase. 4-(Benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-[1,3,5]triazin-2-ol (14d) exhibited low nanomolar potency in the in vitro enzyme inhibition assay (IC(50) = 18 nM) and submicromolar inhibitory activity in a KDR-induced MAP kinase autophosphorylation assay in HUVEC cells (IC(50) = 280 nM), and also demonstrated good in vitro selectivity against a panel of growth factor receptor tyrosine kinases. Further, 14d showed antiangiogenic activity in an aortic ring explant assay by blocking endothelial outgrowths in rat aortas with an IC(50) of 1 microM.
Baindur
Nand
N
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, New Jersey 08512, USA.
Chadha
Naresh
N
Brandt
Benjamin M
BM
Asgari
Davoud
D
Patch
Raymond J
RJ
Schalk-Hihi
Celine
C
Carver
Theodore E
TE
Petrounia
Ioanna P
IP
Baumann
Christian A
CA
Ott
Heidi
H
Manthey
Carl
C
Springer
Barry A
BA
Player
Mark R
MR
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D052160:Benzothiazoles; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009924:Organ Culture Techniques; D010766:Phosphorylation; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*
C500056:4-(benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-(1,3,5)triazin-2-ol; D020533:Angiogenesis Inhibitors; D052160:Benzothiazoles; D013844:Thiazoles; D014227:Triazines; D040301:Vascular Endothelial Growth Factor Receptor-2