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.
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
Margaret M
MM
Faul
James R
JR
Gillig
Michael R
MR
Jirousek
Lawrence M
LM
Ballas
Theo
T
Schotten
Astrid
A
Kahl
Michael
M
Mohr
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