Synthesis and biological evaluation of tricyclic anilinopyrimidines as IKKbeta inhibitors.
A series of tricyclic anilinopyrimidines were synthesized and evaluated as IKKbeta inhibitors. Several analogues, including tricyclic phenyl (10, 18a, 18c, 18d, and 18j) and thienyl (26 and 28) derivatives were shown to have good in vitro enzyme potency and excellent cellular activity. Pharmaceutical profiling of a select group of tricyclic compounds compared to the non-tricyclic analogues suggested that in some cases, the improved cellular activity may be due to increased clog P and permeability.
Crombie
Aimee L
AL
Chemical Sciences, Pfizer Global Research and Development, Collegeville, PA 19335, USA. aimeecrombie@hotmail.com
Sum
Fuk-Wah
FW
Powell
Dennis W
DW
Hopper
Darrin W
DW
Torres
Nancy
N
Berger
Dan M
DM
Zhang
Yixian
Y
Gavriil
Maria
M
Sadler
Tammy M
TM
Arndt
Kim
K
D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011743:Pyrimidines; D051550:I-kappa B Kinase