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5-Aminomethylbenzimidazoles as potent ITK antagonists

2009; Elsevier BV; Volume: 19; Issue: 6 Linguagem: Inglês

10.1016/j.bmcl.2009.02.012

1464-3405

Doris Riether, Renée Zindell, Jennifer A. Kowalski, Brian N. Cook, Jörg Bentzien, Stéphane De Lombaert, David Thomson, Stanley Kugler, Donna Skow, Leslie Martin, Ernest Raymond, Hnin Hnin Khine, Kathy O’Shea, Joseph R. Woska, Deborah D. Jeanfavre, Rosemarie Sellati, Kerry L. M. Ralph, Jennifer Ahlberg, Gabriel Labissiere, Mohammed A. Kashem, Steven S. Pullen, Hidenori Takahashi,

Protein Kinase Regulation and GTPase Signaling

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.