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2-Aminobenzimidazoles as potent ITK antagonists: de novo design of a pyrrole system targeting additional hydrogen bonding interaction |
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| Authors: | Ho Yin Lo,Jö rg Bentzien,Chuk C. Man,Steven S. Pullen,Josephine King,John P. Wolak,Gregory P. Roth |
| Affiliation: | a Boehringer Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA b Boehringer Ingelheim Pharmaceuticals Inc., Immunology and Inflammation, 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA c Boehringer Ingelheim Pharmaceuticals Inc., Biomolecular screening, 900 Ridgebury Rd./PO Box 368, Ridgefield, CT 06877, USA d Burnham Institute for Medical Research at Lake Nona, Orlando, FL 32819, USA |
| Abstract: | Based on information from molecular modeling, a series of 2-aminobenzimidazoles with pyrrole moieties were designed and synthesized as ITK antagonists. Results showed that a significant improvement of intrinsic and cell-based potency was achieved. X-ray crystallographic analysis of an inhibitor complex with ITK confirmed the prediction from the de novo design that the pyrrole moiety of the inhibitor would form an additional hydrogen bonding interaction with Glu436 in the catalytic domain, and hence improve overall binding affinity of the inhibitor. |
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