Several mGluR5 negative allosteric modulators (NAMs) containing an alkyne as a key structural motif are being evaluated in the clinic, including mavoglurant for fragile X syndrome (FXS), dipraglurant for levodopa-induced dyskinesia in Parkinson's disease (LID-PD) and dystonia, and RO4917523 for FXS and depression. The termination of the development of ADX10059 due to liver function abnormalities in clinical studies for chronic indications motivated the exploration of alternative chemotypes lacking the alkyne moiety. We wish to report the discovery of pyrimidine derivatives, a novel series of mGluR5 NAMs, which demonstrated tractable SAR and good potency in vitro. A representative compound from this series has good in silico CNS drug-like properties (MW 356, tPSA 72�, cLogP 2.4, MPO 5.8), had Ki value of 31 nM and IC50 value of 4.2 nM in human mGluR5 binding and functional assays, respectively.

Pyrimidine derivatives as mGlu5 receptor negative allosteric modulators

248th National Meeting (2014)

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