title: 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.
authors.affiliation: Cerecor Inc. Baltimore Maryland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Garner
authors.affiliation: Cerecor Inc. Baltimore Maryland.
authors.forename: Shobha
authors.initials: S
authors.lastname: Gopalakrishnan
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Bednar
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Gaul
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Kiss
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Shil
authors.initials: S
authors.lastname: Patel
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Christine
authors.initials: C
authors.lastname: Fandozzi
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Armando
authors.initials: A
authors.lastname: Lagrutta
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Richard
authors.initials: R
authors.lastname: Briscoe
authors.affiliation: Merck Sharp & Dohme Corp. West Point Pennsylvania.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
authors.affiliation: Cerecor Inc.Baltimore Maryland; Johns Hopkins University School of Medicine Baltimore Maryland.
authors.forename: Blake M
authors.initials: BM
authors.lastname: Paterson
authors.affiliation: Cerecor Inc.Baltimore Maryland; Johns Hopkins University School of Medicine Baltimore Maryland.
authors.forename: James J
authors.initials: JJ
authors.lastname: Vornov
authors.affiliation: Cerecor Inc.Baltimore Maryland; Johns Hopkins University School of Medicine Baltimore Maryland.
authors.forename: Reza
authors.initials: R
authors.lastname: Mazhari
keywords: Depression; GluN2B; NMDA antagonist; major depressive disorder