3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3

  • Bioorg Med Chem Lett. 2004 Jun 21;14(12):3245-50. doi: 10.1016/j.bmcl.2004.03.090.
Han-Cheng Zhang  1 ,  Hong Ye ,  Bruce R Conway ,  Claudia K Derian ,  Michael F Addo ,  Gee-Hong Kuo ,  Leonard R Hecker ,  Diane R Croll ,  Jian Li ,  Lori Westover ,  Jun Z Xu ,  Richard Look ,  Keith T Demarest ,  Patricia Andrade-Gordon ,  Bruce P Damiano ,  Bruce E Maryanoff
Affiliations
  • 1. Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. [email protected]
PMID: 15149684 DOI: 10.1016/j.bmcl.2004.03.090
Abstract

A novel series of acyclic 3-(7-azaindolyl)-4-(aryl/heteroaryl)maleimides was synthesized and evaluated for activity against GSK-3beta and selectivity versus PKC-betaII, as well as a broad panel of protein kinases. Compounds 14 and 17c potently inhibited GSK-3beta (IC(50)=7 and 26 nM, respectively) and exhibited excellent selectivity over PKC-betaII (325 and >385-fold, respectively). Compound 17c was also highly selective against 68 Other protein kinases. In a cell-based functional assay, both 14 and 17c effectively increased glycogen synthase activity by inhibiting GSK-3beta.