5-Aminomethyl-1H-benzimidazoles as orally active inhibitors of inducible T-cell kinase (Itk).
A series of novel 5-aminomethyl-1H-benzimidazole based inhibitors of Itk were prepared. Structure-activity relationships, selectivity and cell activity are reported for this series. Compound 2, a potent and selective antagonist of Itk, inhibited anti-CD3 antibody induced IL-2 production in vivo in mice.
Winters
Michael P
MP
Johnson & Johnson Pharmaceutical Research and Development, 665 Stockton Drive, Exton, PA 19341, USA.
Robinson
Darius J
DJ
Khine
Hnin Hnin
HH
Pullen
Steven S
SS
Woska
Joseph R
JR
Raymond
Ernest L
EL
Sellati
Rosemarie
R
Cywin
Charles L
CL
Snow
Roger J
RJ
Kashem
Mohammed A
MA
Wolak
John P
JP
King
Josephine
J
Kaplita
Paul V
PV
Liu
Lisa H
LH
Farrell
Thomas M
TM
DesJarlais
Renee
R
Roth
Gregory P
GP
Takahashi
Hidenori
H
Moriarty
Kevin J
KJ
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D017252:CD3 Complex / Q000096:biosynthesis; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology
D001562:Benzimidazoles; D017252:CD3 Complex; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase