Contribution of indazolinone tautomers to kinase activity.
The design and synthesis of indazolinone containing kinase inhibitors are reported. Regioisomers that showed profound potency variation in previously-reported isoindolinone and aminoindazole systems were surprisingly found to have similar potencies in the case of the indazolinone chemical series. An interpretation using differential hinge hydrogen bonding and tautomeric equilibrium of indazolinone ring system is supported by quantum mechanics calculations. The equipotent inhibition of a representative kinase (KDR) by regioisomeric indazolinones 4 and 5 is clear evidence that in case of the indazolinone hinge, both tautomers are equally favored, and should be considered in design of inhibitors.
Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, United States. Anil.Vasudevan@abbott.com
Anil
A
Vasudevan
Mary K
MK
Verzal
Clara I
CI
Villamil
Kent D
KD
Stewart
Cele
C
Abad-Zapatero
Tetsuro
T
Oie
Stevan W
SW
Djuric
D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007536:Isomerism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D007191:Indazoles; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2