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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 |
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| Authors: | Leyi Gong Xiaochun Han Tania Silva Yun-Chou Tan Bindu Goyal Parch Tivitmahaisoon Alejandra Trejo Wylie Palmer Heather Hogg Alam Jahagir Muzaffar Alam Paul Wagner Karin Stein Lubov Filonova Brad Loe Ferenc Makra David Rotstein Lubica Rapatova David Goldstein |
| Institution: | 1. Department of Medicinal Chemistry, Roche Palo Alto, Palo Alto, CA 94304, USA;2. Inflammation Therapeutic Area, Roche Palo Alto, Palo Alto, CA 94304, USA;3. Department of Discovery Technologies, Roche Palo Alto, Palo Alto, CA 94304, USA |
| Abstract: | 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. |
| Keywords: | JNK JNK inhibitors Aminopyrimidine c-Jun N-terminus kinase Kinase inhibitors |
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