ABSTRACT
A series of novel 5-aminomethyl-1H-benzimidazole based inhibitors of Itk were prepared. Structure-activity relationships, selectivity and cell activity are reported for this series. Compound 2, a potent and selective antagonist of Itk, inhibited anti-CD3 antibody induced IL-2 production in vivo in mice.
Subject(s)
Benzimidazoles/administration & dosage , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis , Chemistry, Pharmaceutical/methods , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/chemistry , Administration, Oral , Animals , Benzimidazoles/pharmacology , CD3 Complex/biosynthesis , Drug Design , Humans , Inhibitory Concentration 50 , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Models, Chemical , Structure-Activity Relationship , T-Lymphocytes/cytologyABSTRACT
Previously, we reported a series of novel benzimidazole based Itk inhibitors that exhibited excellent enzymatic potency and selectivity but low microsomal stability. Employing a structure based approach a new series of inhibitors with comparable potency and selectivity to the original series and with a potential for improved microsome stability was identified.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Microsomes, Liver/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/chemistry , Adenosine Triphosphate/chemistry , Administration, Oral , Binding Sites , CD3 Complex/chemistry , Crystallography, X-Ray/methods , Drug Design , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Microsomes, Liver/chemistry , Structure-Activity Relationship , T-Lymphocytes/metabolismABSTRACT
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.
