Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors

Autor:	Hnin Hnin Khine, Christopher Ronald Sarko, Mohammed A. Kashem, Noel S. Wilson, John P. Wolak, Josephine King, Teresa Roma, Charles L. Cywin, Jennifer A. Kowalski, Scot Campbell, John Lord, Steven S. Pullen, Michael P. Winters, Gregory P. Roth, Asitha Abeywardane, Roger J. Snow
Rok vydání:	2007
Předmět:	Benzimidazole Stereochemistry High-throughput screening Chemistry Pharmaceutical Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Plasma protein binding Biochemistry chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship Adenosine Triphosphate Drug Discovery Structure–activity relationship Humans Binding site Enzyme Inhibitors Molecular Biology Protein Kinase Inhibitors chemistry.chemical_classification Binding Sites biology Organic Chemistry Hydrogen Bonding Hit to lead Protein-Tyrosine Kinases Enzyme chemistry Models Chemical Enzyme inhibitor biology.protein Molecular Medicine Benzimidazoles Protein Binding
Zdroj:	Bioorganicmedicinal chemistry letters. 17(13)
ISSN:	0960-894X
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3017ea619ea79276e05159f9c76588ec https://pubmed.ncbi.nlm.nih.gov/17499505 Zobrazit plný text záznamu Full Text from ScienceDirect