Schizophrenia is a debilitating illness which affects approximately 1% of the population.  While current therapeutics, based on dopamine 2 (D2) inhibition, are highly effective at treating the positive symptoms of schizophrenia, they are of limited utility in addressing the negative and cognitive symptoms.   It has been suggested that loss of N-methyl-D-aspartate (NMDA) receptor function may give rise to schizophrenia symptomology.  Activation of NMDA receptors is mediated by metabotropic glutamate receptor 5 (mGluR5) which is co-expressed with them on GABA interneurons.  High throughput screening identified a novel, potent positive allosteric modulator (PAM) of mGluR5.  Optimization of the chemotype led to compounds with exquisite potency and a range of mGluR5 pharmacology profiles (high fold shift PAMs, low fold shift PAMs, and Ago-PAMs).  Interrogation of these leads resulted in the identification of BMS-955829, a low fold shift PAM with efficacy in rodent cognition models and a favorable preclinical safety profile.

Discovery of BMS-955829, a potent positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5) for the treatment of schizophrenia

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.