Discovery, Synthesis, and Characterization of an Orally Bioavailable, Brain Penetrant Inhibitor of Mixed Lineage Kinase 3

• Published in: Journal of medicinal chemistry Vol. 56; no. 20; pp. 8032 - 8048
• Main Authors: Goodfellow, Val S, Loweth, Colin J, Ravula, Satheesh B, Wiemann, Torsten, Nguyen, Thong, Xu, Yang, Todd, Daniel E, Sheppard, David, Pollack, Scott, Polesskaya, Oksana, Marker, Daniel F, Dewhurst, Stephen, Gelbard, Harris A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.10.2013
• Subjects: Administration, Oral; Animals; Area Under Curve; Biological Availability; Blood-Brain Barrier - metabolism; Brain - metabolism; Carbazoles - chemical synthesis; Carbazoles - pharmacokinetics; Carbazoles - pharmacology; Cells, Cultured; Cognition Disorders - complications; Cognition Disorders - prevention & control; Drug Discovery - methods; HIV Infections - complications; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Male; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinase Kinase 11; Models, Chemical; Molecular Structure; Monocytes - drug effects; Monocytes - metabolism; Phosphorylation - drug effects; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; tat Gene Products, Human Immunodeficiency Virus - pharmacology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401094t

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.