MAOB
Amine oxidase [flavin-containing] B (EC 1.4.3.4) (Monoamine oxidase type B) (MAO-B)
Publications[править]
Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.
MeSH Terms
- Aging
- Alzheimer Disease
- Animals
- Behavior, Animal
- Brain
- Disease Models, Animal
- Enzyme Inhibitors
- Epigenesis, Genetic
- Female
- Gene Expression
- Hippocampus
- Histone Demethylases
- Humans
- Male
- Memory Disorders
- Mice
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Monoamine Oxidase Inhibitors
- Oxadiazoles
- Rats
- Rats, Sprague-Dawley