Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK.
The design, synthesis, and the biological evaluation of 2-benzamido-pyrimidines as novel IKK inhibitors are described. By optimization of the lead compound 3, compounds 16 and 24 are identified as good inhibitors of IKK2 with IC(50) values of 40 and 25 nM, respectively. Compound 16 also demonstrated significant in vivo activity in an acute model of cytokine release.
Waelchli
Rudolf
R
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. rudolf.waelchli@novartis.com
Bollbuck
Birgit
B
Bruns
Christian
C
Buhl
Thomas
T
Eder
Jörg
J
Feifel
Roland
R
Hersperger
Rene
R
Janser
Philipp
P
Revesz
Laszlo
L
Zerwes
Hans-Günter
HG
Schlapbach
Achim
A
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D016207:Cytokines; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D051550:I-kappa B Kinase