Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors.
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
Snow
Roger J
RJ
Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. rsnow@rdg.boehringer-ingelheim.com <rsnow@rdg.boehringer-ingelheim.com>
Abeywardane
Asitha
A
Campbell
Scot
S
Lord
John
J
Kashem
Mohammed A
MA
Khine
Hnin Hnin
HH
King
Josephine
J
Kowalski
Jennifer A
JA
Pullen
Steven S
SS
Roma
Teresa
T
Roth
Gregory P
GP
Sarko
Christopher R
CR
Wilson
Noel S
NS
Winters
Michael P
MP
Wolak
John P
JP
Cywin
Charles L
CL
D000255:Adenosine Triphosphate / Q000737:chemistry; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase