We describe a clinical candidate molecule from a new series of GluN2B-selective inhibitors that shows enhanced inhibition at extracellular acidic pH values relative to physiological pH. This property should render these compounds more effective inhibitors of NMDA receptors at synapses responding to a high frequency of action potentials, since glutamate-containing vesicles are acidic within their lumen. In addition, acidification of penumbral regions around ischemic tissue should also enhance selective drug action for improved neuroprotection. The aryl piperazine we describe here shows strong neuroprotective actions with minimal side effects in preclinical studies. The clinical candidate molecule, NP10679, has high oral bioavailability with good brain penetration, and is suitable for both intravenous and oral dosing for therapeutic use in man. SIGNIFICANCEThis study identifies a new series of GluN2B-selective negative allosteric modulators with properties appropriate for clinical advancement. The compounds are more potent at acidic pH associated with ischemic tissue, and this property should increase the therapeutic safety of this class by improving efficacy in affected tissue while sparing NMDA receptor block in healthy brain.