Glutamate is the main excitatory neurotransmitter in the brain. It acts on two distinct classes of receptors, the ionotropic (NMDA, AMPA, kainate) and metabotropic glutamate (mGlu) receptors. The metabotropic glutamate receptors play an important modulatory role in neurotransmission and are closely involved in a variety of physiological functions. Preclinical data support the therapeutic potential of negative allosteric modulation of the mGlu2 receptor in neuropsychiatric disorders such as depression and improvement in cognitive function in disorders like Alzheimer Disease.<br/>A high throughput screening (HTS) campaign resulted in attractive pyrazole hits with moderate potency as negative allosteric modulators of the metabotropic glutamate 2 receptor (mGlu2 NAM’s). A focused medicinal chemistry optimization effort led to the identification of mGlu2 NAM compounds with nanomolar potency. Structure-activity Relationships (SAR), ADME properties and <i>in vivo</i> data will be presented and discussed more in detail.

Design of mGlu2 negative allosteric modulators for the treatment of neuropsychiatric disorders

253rd National Meeting (2017)

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