title: Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors.
abstract: 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.
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. rsnow@rdg.boehringer-ingelheim.com <rsnow@rdg.boehringer-ingelheim.com>
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Snow
authors.forename: Asitha
authors.initials: A
authors.lastname: Abeywardane
authors.forename: Scot
authors.initials: S
authors.lastname: Campbell
authors.forename: John
authors.initials: J
authors.lastname: Lord
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Kashem
authors.forename: Hnin Hnin
authors.initials: HH
authors.lastname: Khine
authors.forename: Josephine
authors.initials: J
authors.lastname: King
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kowalski
authors.forename: Steven S
authors.initials: SS
authors.lastname: Pullen
authors.forename: Teresa
authors.initials: T
authors.lastname: Roma
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Roth
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Sarko
authors.forename: Noel S
authors.initials: NS
authors.lastname: Wilson
authors.forename: Michael P
authors.initials: MP
authors.lastname: Winters
authors.forename: John P
authors.initials: JP
authors.lastname: Wolak
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
mesh_terms: 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
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase