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

Structure guided optimization led to a potent series of JNK inhibitors with good physicochemical properties and desirable kinase selectivity as exemplified by compound 17. A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selec...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 23; no. 12; pp. 3565 - 3569
Main Authors:	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, Porto, Joseph Dal, Wong, Brian, Jin, Sue, Chang, Alice, Tran, Patricia, Hsieh, Gary, Niu, Linghao, Shao, Ada, Reuter, Deborah, Hermann, Johaness, Kuglstatter, Andreas, Goldstein, David
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 15-06-2013
Subjects:	Aminopyrimidine c-Jun N-terminus kinase Crystallography, X-Ray Indazoles - chemistry Indazoles - pharmacology Indoles - chemistry Indoles - pharmacology inhibitory concentration 50 JNK JNK inhibitors JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors JNK Mitogen-Activated Protein Kinases - chemistry Kinase inhibitors mitogen-activated protein kinase pharmacokinetics Phosphorylation physicochemical properties Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyrimidines - chemistry Pyrimidines - pharmacology Structure-Activity Relationship JNK inhibitors Aminopyrimidine Kinase inhibitors JNK c-Jun N-terminus kinase
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Summary:	Structure guided optimization led to a potent series of JNK inhibitors with good physicochemical properties and desirable kinase selectivity as exemplified by compound 17. 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 3nM for JNK1 and 20nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Bibliography:	http://dx.doi.org/10.1016/j.bmcl.2013.04.029 SourceType-Other Sources-1 content type line 63 ObjectType-Correspondence-1 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.04.029