Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCbeta.
The synthesis and structure-activity relationship (SAR) trends of a new class of N-(azacycloalkyl)bisindolylmaleimides 1, acyclic derivatives of staurosporine, is described. The representative compound for this series (1e) exhibits an IC(50) of 40-50 nM against the human PKCbeta(1) and PKCbeta(2) isozymes and selectively inhibits the PKCbeta isozymes in comparison to other PKC isozymes (alpha, gamma, delta, epsilon, lambda, and eta). The series is also kinase selective for PKC in comparison to other ATP-dependent kinases. A comparison of the PKC isozyme and kinase activity of the series is made to the kinase inhibitor staurosporine.
Faul
Margaret M
MM
Global Chemical Process Research and Development Division, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA. faul_margaret_m@lilly.com
Gillig
James R
JR
Jirousek
Michael R
MR
Ballas
Lawrence M
LM
Schotten
Theo
T
Kahl
Astrid
A
Mohr
Michael
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D008301:Maleimides / Q000737:chemistry* / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019311:Staurosporine; C088060:bisindolylmaleimide