Synthesis of anilino-monoindolylmaleimides as potent and selective PKCbeta inhibitors.
We report herein synthesis of PKCbeta-selective inhibitors possessing the novel pharmacophore of anilino-monoindolylmaleimide. Several compounds of this series exhibited IC50's as low as 50 nM against human PKCbeta2. One of the most potent compounds, 6l, inhibited PKCbeta1 and PKCbeta2 with IC50 of 21 and 5 nM, respectively, and exhibited selectivity of more than 60-fold in favor of PKCbeta2 relative to other PKC isozymes (PKCalpha, PKCgamma, and PKCepsilon).
Tanaka
Masahiro
M
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Sagawa
Shoichi
S
Hoshi
Jun-ichi
J
Shimoma
Fumito
F
Matsuda
Isamu
I
Sakoda
Kenji
K
Sasase
Tomohiko
T
Shindo
Masanori
M
Inaba
Takashi
T
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry; D064546:Protein Kinase C beta; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D011493:Protein Kinase C; D064546:Protein Kinase C beta