Phase 1 Clinical Results for NP10679, a pH-sensitive GluN2B-selective N-methyl-d-aspartate Receptor Inhibitor

NP10679 is a context-dependent and subunit-selective negative allosteric modulator of N-methyl-d-aspartate (NMDA) receptors. It is a more potent inhibitor of GluN2B-containing NMDA receptors at the acidic levels of extracellular pH (eg, 6.9) found in the penumbral regions associated with cerebral ischemia than at physiological pH. This property allows NP10679 to act selectively in ischemic tissue while minimizing the nonselective blockade of NMDA receptors in healthy brain, thereby reducing on-target adverse effects. We report the results of a first-in-human pharmacokinetic and safety phase 1 clinical trial in healthy volunteers receiving single or multiple doses of NP10679 (NCT04007263). We found that NP10679 was well-tolerated and with a half-life of 20 hours, which is amenable to once per day dosing. The only notable side effect in this clinical trial was modest somnolence at higher doses, atypical in that the subject could easily be aroused. The overall results suggest that NP10679 is a candidate for further development for use in acute brain injury, such as ischemic stroke or aneurysmal subarachnoid hemorrhage, as well as for use in neuropsychiatric indications.