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

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 (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 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 (ED 50) of 0.3-0.7 mg kg(-1) (RO, 30-50%); increase in locomotor activity was observed at ED 50 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 T max of ~1 h and t 1/2 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.

Keywords: Depression; GluN2B; NMDA antagonist; major depressive disorder.

Figure 1

Structure of CERC‐301.

Figure 2

(A) Time course of N‐methyl‐D‐aspartate (NMDA) receptor inhibition by CERC‐301 at three concentrations of 30, 100, and 300 nmol L⁻¹. Drug was applied at time = 0 min. Mean current amplitudes (measured as the peak current during the −20 mV step) measured before and during the exposure to drug (concentrations indicated on plot) are plotted versus time. Current amplitudes were normalized to the peak current evoked in the absence of drug. (B) Dissociation experiments: time course of recovery from CERC‐301 inhibition. Currents were normalized to control current amplitude in the presence of 10 μmol L⁻¹ glutamate and 10 μmol L⁻¹ glycine.

Figure 3

In‐vivo efficacy and potential central nervous system (CNS) side effects of CERC‐301 when orally administered in rats. Efficacy is depicted by a reduction in immobility frequency (filled circles; left axis) during the forced swim test. Potential CNS side effect is depicted by an increase in total distance traveled (open squares; right axis) as a function of dose. A dose‐response curve (solid and dashed lines) was fitted to each mean dataset to calculate efficacious dose (ED ₅₀), corresponding CERC–301 plasma concentration (in ng mL⁻¹ and nmol L⁻¹), and the estimated receptor occupancy (RO). Data are presented as mean ± SD; **P < 0.01. V, vehicle.

Figure 4

Effects of a single oral dose of CERC‐301 on systolic blood pressure. (A) Vehicle subtracted mean changes from time‐controled baseline is shown. (B) Peak change from baseline, vehicle subtracted is shown for each dose of CERC‐301, with or without atenolol and prozasin. All data represented as mean ± SEM, with N = 6 for each group.

Figure 5

Plasma CERC‐301 concentration‐time profile in healthy male subjects. (A) Single doses of 2 to 20 mg fasted. (B) Comparison of fasted versus fed at 4 mg dose. Data are presented as mean ± SD.