5-Aminomethylbenzimidazoles as potent ITK antagonists

Autor:	Stanley Kugler, Mohammed A. Kashem, Ernest L. Raymond, Hidenori Takahashi, Steven S. Pullen, Leslie Martin, Gabriel Labissiere, Jennifer Ahlberg, Jennifer A. Kowalski, Hnin Hnin Khine, Joseph R. Woska, Stéphane De Lombaert, Donna Skow, David S. Thomson, Kathy O’Shea, Brian Nicholas Cook, Renee Zindell, Deborah D. Jeanfavre, Doris Riether, Jörg Bentzien, Kerry L. M. Ralph, Rosemarie Sellati
Rok vydání:	2009
Předmět:	CD3 Complex Stereochemistry Chemistry Pharmaceutical Clinical Biochemistry Pharmaceutical Science Biochemistry Rats Sprague-Dawley chemistry.chemical_compound Inhibitory Concentration 50 Mice Structure-Activity Relationship Benzylamine Amide Drug Discovery Potency Structure–activity relationship Moiety Animals Humans Enzyme Inhibitors Benzamide Molecular Biology chemistry.chemical_classification Mice Inbred BALB C Organic Chemistry Aromatic amine Protein-Tyrosine Kinases Rats chemistry Drug Design Hepatocytes Molecular Medicine Benzimidazoles Female Linker
Zdroj:	Bioorganicmedicinal chemistry letters. 19(6)
ISSN:	1464-3405
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1df8326828e0236a2add4a210c4153e https://pubmed.ncbi.nlm.nih.gov/19246196 Zobrazit plný text záznamu Full Text from ScienceDirect