The identification and development of two novel series of mGluR5 negative allosteric modulators (NAMs) targeting a therapy for Parkinson Disease L-dopa-induced Dyskinesia will be presented.  The advancement of two leads from high-throughput-screens was achieved using structure-activity relationships coupled with balancing physicochemical and pharmacokinetic properties.  Each series was rapidly explored from pyrazolopyrazine and morpholinopyrimidone templates that allowed for late-stage diversification via parallel medicinal chemistry and custom analog synthesis.   These efforts led to the discovery of potent, selective, and orally bioavailable mGluR5 NAMs from alkyne-lacking chemotypes that were advanced into in vivo toxicology studies.

Discovery of novel mGluR5 negative allosteric modulators from structurally distinct chemotypes with pyrazolopyrazine and morpholinopyrimidone cores

247th National Meeting (2014)

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