ABSTRACT
A novel series of N-pyridyl amides as potent p38alpha kinase inhibitors is described. Based on the structural similarities between the initial hit and a well-known imidazole pyrimidine series of p38alpha inhibitors, potencies within the newly discovered series were quickly improved by installation of an (S)-alpha-methylbenzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to p38alpha were evaluated against SAR findings and provided rationale for further development of this series of molecules.
Subject(s)
Amides/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Amides/chemistry , Drug Discovery , Models, Molecular , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
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
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.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Indoles/chemical synthesis , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , Humans , Indoles/pharmacology , Inhibitory Concentration 50 , Structure-Activity Relationship , p38 Mitogen-Activated Protein KinasesABSTRACT
A molecular equivalence number (meqnum) classifies a molecule with respect to a class of structural features or topological shapes such as its cyclic system or its set of functional groups. Meqnums can be used to organize molecular structures into nonoverlapping, yet highly relatable classes. We illustrate the construction of some different types of meqnums and present via examples some methods of comparing diverse chemical libraries based on meqnums. In the examples we compare a library which is a random sample from the MDL Drug Data Report (MDDR) with a library which is a random sample from the Available Chemical Directory (ACD). In our analyses, we discover some interesting features of the topological shape of a molecule and its set of functional groups that are strongly linked with compounds occurring in the MDDR but not in the ACD. We also illustrate the utility of molecular equivalence indices in delineating the structural domain over which an SAR conclusion is valid.
