Abstract
Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compound inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compound 1 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compound 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Area Under Curve
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Biological Availability
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Blood-Brain Barrier / metabolism
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Brain / metabolism
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Carbazoles / chemical synthesis
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Carbazoles / pharmacokinetics
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Carbazoles / pharmacology
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Cells, Cultured
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Cognition Disorders / complications
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Cognition Disorders / prevention & control
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Drug Discovery / methods*
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HIV Infections / complications
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase Kinases / antagonists & inhibitors*
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MAP Kinase Kinase Kinases / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinase Kinase Kinase 11
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Models, Chemical
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Molecular Structure
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Monocytes / drug effects
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Monocytes / metabolism
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Pyridines / chemical synthesis
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Pyrroles / chemical synthesis
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology*
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Tumor Necrosis Factor-alpha / metabolism
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tat Gene Products, Human Immunodeficiency Virus / pharmacology
Substances
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Carbazoles
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Protein Kinase Inhibitors
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Pyridines
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Pyrroles
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Tumor Necrosis Factor-alpha
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URMC-099
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tat Gene Products, Human Immunodeficiency Virus
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3,9-bis((ethylthio)methyl)-K-252a
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases