학술논문
Discovery, Synthesis, andCharacterization of an Orally Bioavailable, Brain Penetrant Inhibitorof Mixed Lineage Kinase 3.
Document Type
Article
Author
Source
Subject
*KINASES
*DRUG development
*CHEMICAL synthesis
*BIOAVAILABILITY
*ORAL medicine
*PARKINSON'S disease treatment
*COGNITION disorders
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Language
ISSN
0022-2623
Abstract
Inhibitionof mixed lineage kinase 3 (MLK3) is a potential strategy for treatmentof Parkinson’s disease and HIV-1 associated neurocognitivedisorders (HAND), requiring an inhibitor that can achieve significantbrain concentration levels. We report here URMC-099 (1) an orally bioavailable (F= 41%), potent (IC50= 14 nM) MLK3 inhibitor with excellent brain exposure inmouse PK models and minimal interference with key human CYP450 enzymesor hERG channels. The compound inhibits LPS-induced TNFα releasein microglial cells, HIV-1 Tat-induced release of cytokines in humanmonocytes and up-regulation of phospho-JNK in Tat-injected brainsof mice. Compound 1likely functions in HAND preclinicalmodels by inhibiting multiple kinase pathways, including MLK3 andLRRK2 (IC50= 11 nM). We compare the kinase specificityand BBB penetration of 1with CEP-1347 (2). Compound 1is well tolerated, with excellent in vivoactivity in HAND models, and is under investigation for further development. [ABSTRACT FROM AUTHOR]