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Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): Optimization for JNK potency and physicochemical properties

2013; Elsevier BV; Volume: 23; Issue: 12 Linguagem: Inglês

10.1016/j.bmcl.2013.04.029

1464-3405

Leyi Gong, Xiaochun Han, Tania Silva, Yun-Chou Tan, Bindu Goyal, Parch Tivitmahaisoon, Alejandra Trejo, Wylie S. Palmer, Heather Hogg, Alam Jahagir, Muzaffar Alam, Paul Wagner, Karin A. Stein, L. K. FILONOVA, Brad Loe, Ferenc Makra, David S. Rotstein, Lubica Rapatova, James Dunn, Fengrong Zuo, Joseph Dal Porto, Brian Wong, Sue Jin, Alice Y. Chang, Patricia Tran, Gary Hsieh, Linghao Niu, A. Shao, Deborah C. Reuter, Johaness Hermann, A. Kuglstatter, David Goldstein,

Quinazolinone synthesis and applications

A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.