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

作者：Gong Leyi^*; Han Xiaochun; Silva Tania; Tan Yun Chou; Goyal Bindu; Tivitmahaisoon Parch; Trejo Alejandra; Palmer Wylie; Hogg Heather; Jahagir Alam; Alam Muzaffar; Wagner Paul; Stein Karin; Filonova Lubov; Loe Brad; Makra Ferenc; Rotstein David; Rapatova Lubica; Dunn James; Zuo Fengrong; Dal Porto Joseph; Wong Brian; Jin Sue; Chang Alice; Tran Patricia; Hsieh Gary; Niu Linghao; Shao Ada; Reuter Deborah; Hermann Johaness; Kuglstatter Andreas; Goldstein David

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(12): 3565-3569.

DOI：10.1016/j.bmcl.2013.04.029

• JNK
• JNK inhibitors
• Aminopyrimidine
• c-Jun N-terminus kinase
• Kinase inhibitors

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.

• 出版日期2013-6-15