ABSTRACT
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
We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.
