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Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2007 Jul 01; Vol. 17 (13), pp. 3660-5. Date of Electronic Publication: 2007 Apr 25. - Publication Year :
- 2007
-
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.
- Subjects :
- Adenosine Triphosphate chemistry
Benzimidazoles chemical synthesis
Binding Sites
Drug Evaluation, Preclinical methods
Enzyme Inhibitors pharmacology
Humans
Hydrogen Bonding
Inhibitory Concentration 50
Models, Chemical
Protein Binding
Protein Kinase Inhibitors chemistry
Structure-Activity Relationship
Benzimidazoles chemistry
Chemistry, Pharmaceutical methods
Protein Kinase Inhibitors chemical synthesis
Protein-Tyrosine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0960-894X
- Volume :
- 17
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 17499505
- Full Text :
- https://doi.org/10.1016/j.bmcl.2007.04.045