Novel tricyclic inhibitors of IKK2: discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066).
The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.
Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, USA. scott.watterson@bms.com
Scott H
SH
Watterson
Charles M
CM
Langevine
Katy
K
Van Kirk
James
J
Kempson
Junquing
J
Guo
Steven H
SH
Spergel
Jagabandhu
J
Das
Robert V
RV
Moquin
Alaric J
AJ
Dyckman
David
D
Nirschl
Kurt
K
Gregor
Mark A
MA
Pattoli
XiaoXia
X
Yang
Kim W
KW
McIntyre
Guchen
G
Yang
Michael A
MA
Galella
Hollie
H
Booth-Lute
Laishun
L
Chen
Zheng
Z
Yang
David
D
Wang-Iverson
Murray
M
McKinnon
John H
JH
Dodd
Joel C
JC
Barrish
James R
JR
Burke
William J
WJ
Pitts
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
C545117:2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimiazo(4,5-d)pyrrolo(2,3-b)pyridin-7-yl)pyridin-2-yl)methyl)acetamide; D000081:Acetamides; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse