a-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR) mediate fast glutamatergic excitatory neurotransmission throughout the central nervous system.  Changes in AMPAR density and subunit composition dynamically regulate synaptic efficacy underlying adaptive brain functions.  Based on the intimate relationship between AMPAR and N-methyl-D-aspartate receptors (NMDAR) and the hypothesis that schizophrenia fundamentally results from dysfunction in NMDAR glutamatergic neurotransmission, positive allosteric modulation (�potentiation�) of AMPAR may overcome certain cognitive impairments in schizophrenia.  This presentation will discuss the medicinal chemistry strategy, along with the preclinical pharmacology, pharmacokinetics and safety data, that led to the discovery of the novel AMPAR potentiator PF-04958242.   PF-04958242 is currently in late-Phase 1 clinical trials; it has excellent safety, tolerability and pharmacokinetics in both healthy volunteers and subjects with schizophrenia.

PF-04958242: A novel AMPA receptor positive allosteric modulator for the treatment of cognitive impairments associated with schizophrenia

248th National Meeting (2014)

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