title: 5-Aminomethylbenzimidazoles as potent ITK antagonists.
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.
authors.affiliation: Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA.
authors.forename: Doris
authors.initials: D
authors.lastname: Riether
authors.forename: Renée
authors.initials: R
authors.lastname: Zindell
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kowalski
authors.forename: Brian N
authors.initials: BN
authors.lastname: Cook
authors.forename: Jörg
authors.initials: J
authors.lastname: Bentzien
authors.forename: Stéphane De
authors.initials: SD
authors.lastname: Lombaert
authors.forename: David
authors.initials: D
authors.lastname: Thomson
authors.forename: Stanley Z
authors.initials: SZ
authors.lastname: Kugler
authors.forename: Donna
authors.initials: D
authors.lastname: Skow
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Martin
authors.forename: Ernest L
authors.initials: EL
authors.lastname: Raymond
authors.forename: Hnin Hnin
authors.initials: HH
authors.lastname: Khine
authors.forename: Kathy
authors.initials: K
authors.lastname: O'Shea
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Woska
authors.forename: Deborah
authors.initials: D
authors.lastname: Jeanfavre
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Sellati
authors.forename: Kerry L M
authors.initials: KL
authors.lastname: Ralph
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ahlberg
authors.forename: Gabriel
authors.initials: G
authors.lastname: Labissiere
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Kashem
authors.forename: Steven S
authors.initials: SS
authors.lastname: Pullen
authors.forename: Hidenori
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D017252:CD3 Complex / Q000096:biosynthesis; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D017252:CD3 Complex; D004791:Enzyme Inhibitors; C031000:benzimidazole; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase