Preclinical pharmacology and pharmacokinetics of CERC-301, a GluN2B-selective N-methyl-D-aspartate receptor antagonist

Rachel Garner, Shobha Gopalakrishnan, John A. Mccauley, Rodney A. Bednar, Stanley L. Gaul, Scott D. Mosser, Laszlo Kiss, Joseph J. Lynch, Shil Patel, Christine Fandozzi, Armando Lagrutta, Richard Briscoe, Nigel J. Liverton, Blake M. Paterson, James J. Vornov, Reza Mazhari

Research output: Contribution to journalReview articlepeer-review

16 Scopus citations

Abstract

The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (Ki, 8.1 nmol L-1) specific to GluN2B with an IC50 of 3.6 nmol L-1 and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED50) of 0.3-0.7 mg kg-1 (RO, 30-50%); increase in locomotor activity was observed at ED50 of 2 mg kg-1, corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L-1, similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L-1, respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with Tmax of ~1 h and t1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalPharmacology Research and Perspectives
Volume3
Issue number6
DOIs
StatePublished - Dec 1 2015

Keywords

  • Depression
  • GluN2B
  • Major depressive disorder
  • NMDA antagonist

ASJC Scopus subject areas

  • Neurology
  • Pharmacology, Toxicology and Pharmaceutics(all)

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