|
|||||
|
|
5-Aminomethylbenzimidazoles as potent ITK antagonists |
|
| Authors: | Doris Riether Renée Zindell Jennifer A Kowalski Brian N Cook Jörg Bentzien Stéphane De Lombaert David Thomson Stanley Z Kugler Donna Skow Leslie S Martin Ernest L Raymond Hnin Hnin Khine Kathy O’Shea Joseph R Woska Deborah Jeanfavre Rosemarie Sellati Kerry LM Ralph Jennifer Ahlberg Gabriel Labissiere Mohammed A Kashem Hidenori Takahashi |
| Institution: | 1. Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA;2. Inflammation and Immunology Departments, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA;3. Cardiovascular Disease Department, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA;4. Department of Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA |
| Abstract: | 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. |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ | |