Discovery, SAR and X-ray structure of 1H-benzimidazole-5-carboxylic acid cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (Itk).
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
Moriarty
Kevin J
KJ
Johnson & Johnson, PRDUS, LLC, Springhouse, PA 19477, USA.
Takahashi
Hidenori
H
Pullen
Steven S
SS
Khine
Hnin Hnin
HH
Sallati
Rosemarie H
RH
Raymond
Ernest L
EL
Woska
Joseph R
JR
Jeanfavre
Deborah D
DD
Roth
Gregory P
GP
Winters
Michael P
MP
Qiao
Lei
L
Ryan
Declan
D
DesJarlais
Renee
R
Robinson
Darius
D
Wilson
Matthew
M
Bobko
Mark
M
Cook
Brian N
BN
Lo
Ho Yin
HY
Nemoto
Peter A
PA
Kashem
Mohammed A
MA
Wolak
John P
JP
White
André
A
Magolda
Ronald L
RL
Tomczuk
Bruce
B
D000577:Amides / Q000737:chemistry*; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D008956:Models, Chemical; D008968:Molecular Conformation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D013329:Structure-Activity Relationship
C470231:5-benzimidazolecarboxylic acid; D000577:Amides; D001562:Benzimidazoles; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase