5-Aminomethylbenzimidazoles as potent ITK antagonists.
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.
Riether
Doris
D
Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA.
Zindell
Renée
R
Kowalski
Jennifer A
JA
Cook
Brian N
BN
Bentzien
Jörg
J
Lombaert
Stéphane De
SD
Thomson
David
D
Kugler
Stanley Z
SZ
Skow
Donna
D
Martin
Leslie S
LS
Raymond
Ernest L
EL
Khine
Hnin Hnin
HH
O'Shea
Kathy
K
Woska
Joseph R
JR
Jeanfavre
Deborah
D
Sellati
Rosemarie
R
Ralph
Kerry L M
KL
Ahlberg
Jennifer
J
Labissiere
Gabriel
G
Kashem
Mohammed A
MA
Pullen
Steven S
SS
Takahashi
Hidenori
H
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
D001562:Benzimidazoles; D017252:CD3 Complex; D004791:Enzyme Inhibitors; C031000:benzimidazole; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase