Open AccessPreclinical pharmacology and pharmacokinetics of CERC‐301, a GluN2B‐selective N ‐methyl‐D‐aspartate receptor antagonist
Author(s) -
Garner Rachel,
Gopalakrishnan Shobha,
McCauley John A.,
Bednar Rodney A.,
Gaul Stanley L.,
Mosser Scott D.,
Kiss Laszlo,
Lynch Joseph J.,
Patel Shil,
Fandozzi Christine,
Lagrutta Armando,
Briscoe Richard,
Liverton Nigel J.,
Paterson Blake M.,
Vornov James J.,
Mazhari Reza
Publication year - 2015
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.198
Subject(s) - pharmacokinetics , pharmacology , pharmacodynamics , antagonist , bioavailability , chemistry , neurotoxicity , nmda receptor , receptor , medicine , toxicity , biochemistry
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 (Occ 50 ) 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.