| Literature DB >> 19246196 |
Doris Riether1, 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 L M Ralph, Jennifer Ahlberg, Gabriel Labissiere, Mohammed A Kashem, Steven S Pullen, Hidenori Takahashi.
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.Entities:
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Year: 2009 PMID： 19246196 DOI： 10.1016/j.bmcl.2009.02.012
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823