3-9-bis((ethylthio)methyl)-k-252a and HIV-Infections

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.

Topics: Administration, Oral; Animals; Area Under Curve; Biological Availability; Blood-Brain Barrier; Brain; Carbazoles; Cells, Cultured; Cognition Disorders; Drug Discovery; HIV Infections; Humans; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinase Kinase 11; Models, Chemical; Molecular Structure; Monocytes; Phosphorylation; Protein Kinase Inhibitors; Pyridines; Pyrroles; tat Gene Products, Human Immunodeficiency Virus; Tumor Necrosis Factor-alpha

CEP-1347 is a potent inhibitor of mixed lineage kinase (MLK), which was investigated for ameliorating HIV-associated neurocognitive disorders. CEP-1347 and atazanavir pharmacokinetics were determined when CEP-1347 50 mg twice daily was administered to HIV-infected patients (n = 20) receiving combination antiretroviral therapy including atazanavir and ritonavir (ATV/RTV, 300/100 mg) once daily continuously. Co-administration of CEP-1347 and ATV/RTV resulted with significant changes in pharmacokinetics of ATV but not RTV. Specifically, an increase in ATV accumulation ratio of 15 % (p = 0.007) and a prolongation of T(½) from 12.7 to 15.9 h (p = 0.002) were observed. The results suggested that co-administration of CEP-1347 with ATV/RTV in HIV-infected patients might result in limited impact on ATV but not on RTV pharmacokinetics.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Carbazoles; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Half-Life; HIV Infections; HIV-1; Humans; Male; MAP Kinase Kinase Kinases; Middle Aged; Nootropic Agents; Oligopeptides; Protein Kinase Inhibitors; Pyridines; Ritonavir