Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors.
We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50 = 0.30 microM), which however was considerably less potent against IKK-1 (IC50 = 4.0 microM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of 1, we prepared a series of tetracyclic analogues (7, 13, and 18). The synthesis and biological activities of these potent IKK inhibitors are described.
Beaulieu
Francis
F
Bristol-Myers Squibb Pharmaceutical Research Institute, 100 boul. de l'Industrie, Candiac, Que., Canada J5R 1J1. francis.beaulieu@bms.com
Ouellet
Carl
C
Ruediger
Edward H
EH
Belema
Makonen
M
Qiu
Yuping
Y
Yang
Xuejie
X
Banville
Jacques
J
Burke
James R
JR
Gregor
Kurt R
KR
MacMaster
John F
JF
Martel
Alain
A
McIntyre
Kim W
KW
Pattoli
Mark A
MA
Zusi
F Christopher
FC
Vyas
Dolatrai
D
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D001562:Benzimidazoles; D006576:Heterocyclic Compounds, 4 or More Rings; D011799:Quinazolines; D011804:Quinolines; D011810:Quinoxalines; D051550:I-kappa B Kinase