Abstract
Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.
MeSH terms
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Animals
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Blood-Brain Barrier / drug effects
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Chemistry Techniques, Synthetic
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Crystallography, X-Ray
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Cytochrome P-450 Enzyme Inhibitors / chemistry
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Cytochrome P-450 Enzyme Inhibitors / pharmacology
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Disease Models, Animal
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Dogs
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Drug Evaluation, Preclinical / methods
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Half-Life
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Humans
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Huntington Disease / drug therapy
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Huntington Disease / metabolism
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Inhibitory Concentration 50
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Madin Darby Canine Kidney Cells / drug effects
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Mice
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Mitogen-Activated Protein Kinase 10 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 10 / chemistry
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Pyrazoles / chemistry
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Pyrimidines / chemistry
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Structure-Activity Relationship
Substances
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Cytochrome P-450 Enzyme Inhibitors
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Mitogen-Activated Protein Kinase 10
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pyrimidine