Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 Jul;12(7):706-717.
doi: 10.1002/cpdd.1217. Epub 2023 Jan 15.

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

Robert Zaczek  1 , Stephen F Traynelis  2 , Ray Dingledine  2 , George W Koszalka  1 , Daniel T Laskowitz  3
Affiliations
Clinical Trial

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

Robert Zaczek et al. Clin Pharmacol Drug Dev. 2023 Jul.

Abstract

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.

Keywords: NMDA receptor; ischemia; neuroprotection; subarachnoid hemorrhage.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest

DTL serves a consultant for NeuroOp. SFT is a member of the SAB for Eumentis Therapeutics, Sage Therapeutics, and Combined Brain, is a member of the Medical Advisory Board for the GRIN2B Foundation and the CureGRIN Foundation, is an advisor to GRIN Therapeutics, is co-founder of NeurOp Inc. and AgriThera Inc., and is a member of the Board of Directors of NeurOp Inc. RD is a co-founder and member of the Board of Directors for NeurOp, Inc. and Pyrefin, Inc. RZ and GWK have previously been employees of NeurOp Inc. RD and SFT are co-inventors on IP owned by Emory University and licensed to NeurOp.

Figures

Figure 1:
Figure 1:
Plasma exposure of NP10679 after a single IV dose in human subjects. (A) Plasma collection and quantification were performed as described in the Methods. Data presented as ng/mL of NP10679 represent the mean and SD of 6 subjects per dose except for 150 mg, which is the mean of 5 subjects. The inset shows the structure of NP10679, ((R)-6-(2-Hydroxy-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one). (B) Cmax (mean ± SD) as a function of dose (R2=0.919). (C) AUCinf is plotted against the dose, confirming dose linearity (R2=0.996).
Figure 2:
Figure 2:
Plasma Exposure of NP10679 after five daily IV doses administered to human subjects. (A) Plasma collection and quantification were performed as described in Methods. Data presented as ng/mL of NP10679 represent the mean of 6 subjects per dose. (B) AUC0–96h calculated for day 5 is shown for doses administered during the multiple ascending dose trial (R2=0.999). (C) AUC0–24 h is shown for each day (0–24 hrs).
See this image and copyright information in PMC

References

    1. Weiland J, Beez A, Westermaier T, Kunze E, Sirén A-L, Lilla N. Neuroprotective Strategies in Aneurysmal Subarachnoid Hemorrhage (aSAH). Int J Mol Sci. 2021; 22(11): 5442. - PMC - PubMed
    1. Olney JW. Glutamate-induced retinal degeneration in neonatal mice. Electron microscopy of the acutely evolving lesion. J Neuropathol Exp Neurol. 1969; 28(3): 455–474. - PubMed
    1. Choi DW. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci. 1988; 11(10): 465–469. - PubMed
    1. Lipton SA. Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx. 2004; 1(1): 101–110. - PMC - PubMed
    1. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 2010; 62(3): 405–496. - PMC - PubMed

Publication types

Substances

Associated data