ABSTRACT
Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38alpha MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.
Subject(s)
Drug Design , Indoles/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Piperazines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Animals , Dogs , Haplorhini , Humans , Indoles/pharmacokinetics , Mitogen-Activated Protein Kinase 14/metabolism , Piperazine , Piperazines/pharmacokinetics , Protein Binding/drug effects , Protein Binding/physiology , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Secondary , RatsABSTRACT
The design and synthesis of a new class of p38alpha MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38alpha enzymatic and cell-based cytokine TNFalpha production inhibition assays. The optimal linkers between the piperidine and the oxalyl amide were found to be [6,5] fused ring heterocycles. Substituted indoles and azaindoles were favored structural motifs in the cellular assay.
Subject(s)
Amides/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Oxalates/chemistry , Piperidines/chemistry , Amides/metabolism , Amides/pharmacology , Crystallography, X-Ray , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/metabolism , Heterocyclic Compounds/pharmacology , Humans , Mitogen-Activated Protein Kinase 14/metabolism , Oxalates/metabolism , Oxalates/pharmacology , Piperidines/metabolism , Piperidines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacologyABSTRACT
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 10nM to >20microM and were dependant upon both the nature of the aryl group and the tether joining the basic amine to the indolyl maleimide core of the inhibitors. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.
Subject(s)
Benzene Derivatives/pharmacology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Maleimides/pharmacology , Adenosine Triphosphate/metabolism , Benzene Derivatives/chemical synthesis , Binding Sites , Enzyme Inhibitors/chemical synthesis , Hydrophobic and Hydrophilic Interactions , Indoles/chemical synthesis , Maleimides/chemical synthesis , Models, Chemical , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Non-ATP competitive pyrimidine-based inhibitors of CaMKIIdelta were identified. Computational studies were enlisted to predict the probable mode of binding. The results of the computational studies led to the design of ATP competitive inhibitors with optimized hinge interactions. Inhibitors of this class possessed improved enzyme and cellular activity compared to early leads.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Pyrimidines/pharmacology , Adenosine Triphosphate/metabolism , Binding, Competitive , Enzyme Inhibitors/chemical synthesis , Models, Chemical , Pyrimidines/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 34nM to >20microM and were dependant upon both the nature of the aryl group and the hydrogen bond donating potential of the maleimide ring. Key interactions with the kinase ATP site and hinge region were found to be consistent with homology modeling predictions.
Subject(s)
Benzene Derivatives/pharmacology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Maleimides/pharmacology , Adenosine Triphosphate/metabolism , Benzene Derivatives/chemical synthesis , Binding Sites , Enzyme Inhibitors/chemical synthesis , Indoles/chemical synthesis , Maleimides/chemical synthesis , Models, Chemical , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin-dependant kinase. Inhibitory activities against the enzyme ranged from 34nM to >20microM and were dependant upon both the nature of the aryl group and the tether joining the basic amine to the indolyl maleimide core. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.
Subject(s)
Amines/pharmacology , Benzene Derivatives/pharmacology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Maleimides/pharmacology , Adenosine Triphosphate/metabolism , Amines/chemistry , Benzene Derivatives/chemical synthesis , Binding Sites , Enzyme Inhibitors/chemical synthesis , Indoles/chemical synthesis , Maleimides/chemical synthesis , Models, Chemical , Structure-Activity Relationship , Substrate SpecificityABSTRACT
The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Inflammation/drug therapy , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Disease Models, Animal , Enzyme Inhibitors/pharmacokinetics , Female , Granulocytes/drug effects , Granulocytes/metabolism , Guinea Pigs , Humans , In Vitro Techniques , Indoles/pharmacokinetics , Lung/drug effects , Lung/pathology , Male , Mice , Mice, Inbred BALB C , Ovalbumin , Sepsis/drug therapy , Sepsis/physiopathology , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/drug effectsABSTRACT
Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that function within T cells in both normal and stress-related pathophysiological states, including type 1 diabetes. The nonobese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type 1 diabetes in humans. Because p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38alpha MAPK-selective inhibitor, indole-5-carboxamide (SD-169), on the development and progression of type 1 diabetes in the NOD mouse. In preventive treatment studies, SD-169 significantly reduced p38 and HSP60 expression in T cells of the pancreatic beta islets. Following treatment, the incidence of diabetes as determined by blood glucose levels was significantly lower, and immuno-histochemistry of pancreatic beta islet tissue demonstrated significant reduction in CD5+ T cell infiltration in the SD-169 treatment group as compared with untreated NOD mice. In therapeutic studies using mildly and moderately hyperglycemic NOD mice, SD-169 treatment lowered blood glucose and improved glucose homeostasis. Furthermore, following cessation of SD-169 treatment, NOD mice showed significant arrest of diabetes. In conclusion, we report that this p38alpha-selective inhibitor prevents the development and progression of diabetes in NOD mice by inhibiting T cell infiltration and activation, thereby preserving beta cell mass via inhibition of the p38 MAPK signaling pathway. These results have bearing on current prophylactic and therapeutic protocols using p38alpha-selective inhibitors in the prediabetic period for children at high risk of type 1 diabetes, in the honeymoon period, and for adults with latent autoimmune diabetes.
Subject(s)
Diabetes Mellitus, Type 1/enzymology , Diabetes Mellitus, Type 1/prevention & control , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Animals , Diabetes Mellitus, Type 1/drug therapy , Female , Mice , Mice, Inbred NOD , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/pharmacologyABSTRACT
p38alpha Mitogen Activated Protein Kinase (MAP kinase) is an intracellular soluble serine threonine kinase. p38alpha kinase is activated in response to cellular stresses, growth factors and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). The central role of p38alpha activation in settings of both chronic and acute inflammation has led efforts to find inhibitors of this enzyme as possible therapies for diseases such as rheumatoid arthritis, where p38alpha activation is thought to play a causal role. Herein, we report structure-activity relationship studies on a series of indole-based heterocyclic inhibitors that led to the design and identification of a new class of p38alpha inhibitors.
