5-Aminomethylbenzimidazoles as potent ITK antagonists
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- 作者：Doris Riether ; René ; e Zindell ; Jennifer A. Kowalski ; Brian N. Cook ; Jö ; rg Bentzien ; Sté ; phane De Lombaert ; David Thomson ; Stanley Z. Kugler Jr. ; Donna Skow ; Leslie S. Martin ; Ernest L. Ray
- 关键词：ITK ; Interleukin-2 inducible T-cell kinase ; 5-Aminobenzimidazole
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2009
- 出版时间：15 March 2009
- 年：2009
- 卷：19
- 期：6
- 页码：1588-1591
- 全文大小：527 K
文摘
Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described.