Itk kinase inhibitors: initial efforts to improve the metabolical stability and the cell activity of the benzimidazole lead.
Previously, we reported a series of novel benzimidazole based Itk inhibitors that exhibited excellent enzymatic potency and selectivity but low microsomal stability. Employing a structure based approach a new series of inhibitors with comparable potency and selectivity to the original series and with a potential for improved microsome stability was identified.
Moriarty
Kevin J
KJ
Johnson & Johnson, PRDUS, Springhouse, PA 19477, USA.
Winters
Michael
M
Qiao
Lei
L
Ryan
Declan
D
DesJarlis
Renee
R
Robinson
Darius
D
Cook
Brian N
BN
Kashem
Mohammed A
MA
Kaplita
Paul V
PV
Liu
Lisa H
LH
Farrell
Thomas M
TM
Khine
Hnin Hnin
HH
King
Josephine
J
Pullen
Steven S
SS
Roth
Gregory P
GP
Magolda
Ronald
R
Takahashi
Hidenori
H
D000255:Adenosine Triphosphate / Q000737:chemistry; D000284:Administration, Oral; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry*; D001665:Binding Sites; D017252:CD3 Complex / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism
D001562:Benzimidazoles; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; C031000:benzimidazole; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase