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 pref...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-07, Vol.17 (13), p.3660-3665
Hauptverfasser:	Snow, Roger J., Abeywardane, Asitha, Campbell, Scot, Lord, John, Kashem, Mohammed A., Khine, Hnin Hnin, King, Josephine, Kowalski, Jennifer A., Pullen, Steven S., Roma, Teresa, Roth, Gregory P., Sarko, Christopher R., Wilson, Noel S., Winters, Michael P., Wolak, John P., Cywin, Charles L.
Format:	Artikel
Sprache:	eng
Schlagworte:	Adenosine Triphosphate - chemistry Benzimidazole Benzimidazoles - chemical synthesis Benzimidazoles - chemistry Binding Sites Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Chemistry, Pharmaceutical - methods Drug Evaluation, Preclinical - methods Enzyme Inhibitors - pharmacology Humans Hydrogen Bonding Immunomodulators Inducible T cell kinase Inhibitory Concentration 50 ITK Kinase Kinase inhibitor Medical sciences Models, Chemical Pharmacology. Drug treatments Protein Binding Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein-Tyrosine Kinases - antagonists & inhibitors Structure-Activity Relationship
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2007.04.045