|Elimination half-life||30–40 hours|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||418.512 g/mol g·mol−1|
|3D model (JSmol)|
CERC-501 (originally known as LY-2456302) is a selective antagonist of the κ-opioid receptor (KOR) which was originally developed by Eli Lilly and is now under development by Janssen Pharmaceuticals for the treatment of major depressive disorder and substance use disorders including alcoholism, nicotine addiction, and illicit drug dependence.
CERC-501 is a potent, selective, short-acting (i.e., non-"inactivating") antagonist of the KOR (Ki = 0.81 nM vs. 24.0 nM and 155 nM for the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), respectively; approximately 30-fold selectivity for the KOR). The drug has been found to dose-dependently block fentanyl-induced miosis at 25 mg and 60 mg in humans (with minimal to no blockade at doses of 4 to 10 mg), suggesting that the drug significantly occupies and antagonizes the MOR at a dose of at least 25 mg but not of 10 mg or less. However, a more recent study assessing neuroendocrine effects of the drug in normal volunteers and subjects with a history of cocaine dependence reported observations consistent with modest MOR antagonism at the 10 mg dose. In animal models of depression, CERC-501 has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.
Positron emission tomography imaging revealed that brain KORs were almost completely saturated by the drug 2.5 hours following a single dose of 10 mg, which supported the 4 mg to 25 mg dosages that CERC-501 is being explored in clinical trials. Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose. At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg. No serious side effects were observed, and all side effects seen were mild to moderate and not considered to be due to CERC-501.
The oral bioavailability of CERC-501 is 25% and is regarded as good. The drug is rapidly absorbed, with maximal concentrations occurring 1 to 2 hours after administration. It has an elimination half-life of 30 to 40 hours in healthy subjects. The circulating levels of CERC-501 increase proportionally with increasing doses. Steady-state concentrations are reached after 6 to 8 days of once-daily dosing. CERC-501 has been shown to reproducibly penetrate the blood–brain barrier.
In February 2015, Cerecor Inc. announced that they had acquired the rights from Eli Lilly to develop and commercialize LY-2456302 (under the new developmental code name of CERC-501).
As of 2016, CERC-501 has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression. A phase II study of CERC-501 in heavy smokers was commenced in early 2016 and results of the study were expected before the end of 2016. Unfortunately, CERC-501 failed to meet its main endpoint for nicotine withdrawal in the study.
In August 2017, it was announced that Cerecor had sold its rights to CERC-501 to Janssen Pharmaceuticals. Janssen was also experimenting with esketamine for the treatment of depression as of 2017.
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