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
We have recently reported the discovery of a novel class of glucocorticoid receptor (GR) antagonists, exemplified by 3, containing a 1,2-dihydroquinoline molecular scaffold. Further SAR studies of these antagonists uncovered chemical modifications conveying agonist functional activity to this series. These agonists exhibit good GR binding affinity and are selective against other nuclear hormone receptors.
Subject(s)
Quinolines/chemistry , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Quinolines/metabolism , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
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.