Aticaprant
Investigational antidepressant compound
From Wikipedia, the free encyclopedia
Aticaprant, also known by its developmental codes JNJ-67953964, CERC-501, and LY-2456302, is a κ-opioid receptor (KOR) antagonist which was under development for the treatment of major depressive disorder and other conditions.[1][3][4][5] Aticaprant is taken orally.[2]
- None
| |
 | |
| Clinical data | |
|---|---|
| Other names | JNJ-67953964; CERC-501; LY-2456302 |
| Routes of administration | Oral[1][2] |
| Drug class | κ-Opioid receptor antagonist |
| ATC code |
|
| Pharmacokinetic data | |
| Bioavailability | 25%[2] |
| Elimination half-life | 30–40 hours[2] |
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C26H27FN2O2 |
| Molar mass | 418.512 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Side effects of aticaprant include itching, among others.[4][6] Aticaprant acts as a selective antagonist of the KOR, the biological target of the endogenous opioid peptide dynorphin.[3] The medication has decent selectivity for the KOR over the μ-opioid receptor (MOR) and other targets, a relatively long half-life of 30 to 40 hours, and readily crosses the blood–brain barrier to produce central effects.[4][7]
Aticaprant was originally developed by Eli Lilly, was under development by Cerecor for a time, and is now under development by Janssen Pharmaceuticals.[1] As of July 2022, it is in phase III clinical trials for major depressive disorder.[1] In March 2025, Johnson & Johnson discontinued development of aticaprant for major depressive disorder due to lack of effectiveness in phase III trials.[5]
Aticaprant was also under development for the treatment of alcoholism, cocaine use disorder, and nicotine withdrawal, but development for these indications was discontinued as well.[1]
Pharmacology
Pharmacodynamics
Aticaprant 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).[8][9][10] 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.[10] 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.[11] In animal models of depression, aticaprant has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.[12]
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 aticaprant is being explored at in clinical trials.[13][14] Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[15][14] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[15][14] No serious side effects were observed, and all side effects seen were mild to moderate and were not thought to be due to aticaprant.[14]
Pharmacokinetics
The oral bioavailability of aticaprant is 25%.[2] The drug is rapidly absorbed, with maximal concentrations occurring 1 to 2 hours after administration.[2] It has an elimination half-life of 30 to 40 hours in healthy subjects.[2] The circulating levels of aticaprant increase proportionally with increasing doses.[2] Steady-state concentrations are reached after 6 to 8 days of once-daily dosing.[2] Aticaprant has been shown to reproducibly penetrate the blood–brain barrier.[13][14]
History
Aticaprant was originally developed by Eli Lilly under the code name LY-2456302.[1] It first appeared in the scientific literature in 2010 or 2011.[16][17] The compound was first patented in 2009.[18]
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 CERC-501).[19]
As of 2016, aticaprant has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[20][12] A phase II study of aticaprant in heavy smokers was commenced in early 2016 and results of the study were expected before the end of 2016.[14] Aticaprant failed to meet its main endpoint for nicotine withdrawal in the study.[21]
In August 2017, it was announced that Cerecor had sold its rights to aticaprant to Janssen Pharmaceuticals.[22][21] Janssen was also experimenting with esketamine for the treatment of depression as of 2017.[21]
In March 2025, Johnson & Johnson discontinued development of aticaprant for major depressive disorder due to lack of effectiveness in phase 3 trials.[5] It has not completely discontinued aticaprant however and has said that it will continue to evaluate the drug in other areas.[5] A regulatory application for approval of the medication had previously been expected to be submitted by 2025.[1]
Research
In addition to major depressive disorder, aticaprant was under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal.[1] However, development for these indications was discontinued.[1]