Английская Википедия:Aticaprant

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Aticaprant, also known by its developmental codes JNJ-67953964, CERC-501, and LY-2456302, is a κ-opioid receptor (KOR) antagonist which is under development for the treatment of major depressive disorder.[1][2][3] A regulatory application for approval of the medication is expected to be submitted by 2025.[1] Aticaprant is taken by mouth.[4]

Side effects of aticaprant include itching, among others.[3][5] Aticaprant acts as a selective antagonist of the KOR, the biological target of the endogenous opioid peptide dynorphin.[2] 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 40Шаблон:Nbsphours, and readily crosses the blood–brain barrier to produce central effects.[3][6]

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 3 clinical trials for major depressive disorder.[1] Like other kappa opioid antagonists currently under clinical investigation for the treatment of major depression, its efficacy may be compromised by the countervailing activation of pro-inflammatory cytokines in microglia within the CNS.[7]

Aticaprant was also under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal, but development for these indications was discontinued.[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%.[4] The drug is rapidly absorbed, with maximal concentrations occurring 1 to 2 hours after administration.[4] It has an elimination half-life of 30 to 40 hours in healthy subjects.[4] The circulating levels of aticaprant increase proportionally with increasing doses.[4] Steady-state concentrations are reached after 6 to 8 days of once-daily dosing.[4] 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]

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]

See also

References

Шаблон:Reflist

Further reading

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Шаблон:Refend

External links

Шаблон:Opioid receptor modulators

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  1. ↑ 1,0 1,1 1,2 1,3 1,4 1,5 1,6 1,7 Шаблон:Cite web
  2. ↑ 2,0 2,1 Шаблон:Cite book
  3. ↑ 3,0 3,1 3,2 Шаблон:Cite book
  4. ↑ 4,0 4,1 4,2 4,3 4,4 4,5 Шаблон:Cite journal
  5. ↑ Шаблон:Cite journal
  6. ↑ Шаблон:Cite journal
  7. ↑ Шаблон:Cite journal
  8. ↑ Шаблон:Cite journal
  9. ↑ Шаблон:Cite journal
  10. ↑ 10,0 10,1 Шаблон:Cite journal
  11. ↑ Шаблон:Cite journal
  12. ↑ 12,0 12,1 Шаблон:Cite journal
  13. ↑ 13,0 13,1 Шаблон:Cite news
  14. ↑ 14,0 14,1 14,2 14,3 14,4 14,5 Шаблон:Cite journal
  15. ↑ 15,0 15,1 Шаблон:Cite book
  16. ↑ Шаблон:Cite journal
  17. ↑ Шаблон:Cite journal
  18. ↑ Шаблон:Cite web
  19. ↑ Шаблон:Cite web
  20. ↑ Шаблон:Cite book
  21. ↑ 21,0 21,1 21,2 Шаблон:Cite web
  22. ↑ Шаблон:Cite web
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