ATICAPRANT

ATICAPRANT

JNJ-67953964, WHO 10582

1174130-61-0

BENZAMIDE, 4-(4-(((2S)-2-(3,5-DIMETHYLPHENYL)-1-PYRROLIDINYL)METHYL)PHENOXY)-3-FLUORO-

C₂₆H₂₇FN₂O₂,  418.512

• 4-[4-[[(2S)-2-(3,5-Dimethylphenyl)-1-pyrrolidinyl]methyl]phenoxy]-3-fluorobenzamide (ACI)
• (S)-4-(4-((2-(3,5-Dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)-3-fluorobenzamide
• 4-(4-{[(2S)-2-(3,5-dimethylphenyl)pyrrolidin-1-yl]methyl}phenoxy)-3-fluorobenzamide
• Aticaprant
• CERC 501
• JNJ 67953964
• JNJ 67953964AAA
• LY 2456302
• S-Aticaprant
• CERC-501
• JSPA 0658 JSPA-0658 JSPA0658
• LY 2456302 LY-2456302 , LY2456302

• OriginatorEli Lilly and Company
• DeveloperAvalo Therapeutics; Eli Lilly and Company; Johnson & Johnson Innovative Medicine
• ClassAntidepressants; Benzamides; Benzene derivatives; Drug withdrawal therapies; Fluorinated hydrocarbons; Pyrrolidines; Smoking cessation therapies
• Mechanism of ActionOpioid kappa receptor antagonists

• Phase III Major depressive disorder
• DiscontinuedAlcoholism; Cocaine-related disorders; Smoking withdrawal
• 26 Jun 2024Janssen Research & Development initiates a phase III VENTURA-7 trial for Major depressive disorder (Adjunctive treatment) in USA (PO, Tablet) (NCT06514742) (EudraCT2024-511557-21-00)
• 01 Oct 2023Janssen Pharmaceuticals is now called Johnson & Johnson Innovative Medicine (Janssen Pharmaceuticals website, October 2023)
• 19 May 2023Chemical structure information added

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.^[2][3][4] A regulatory application for approval of the medication is expected to be submitted by 2025.^[2] Aticaprant is taken by mouth.^[1]

Side effects of aticaprant include itching, among others.^[4][5] 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][6]

Aticaprant was originally developed by Eli Lilly, was under development by Cerecor for a time, and is now under development by Janssen Pharmaceuticals.^[2] As of July 2022, it is in phase 3 clinical trials for major depressive disorder.^[2] 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.^[2]

Pharmacology

Pharmacodynamics

Aticaprant is a potent, selective, short-acting (i.e., non-“inactivating”) antagonist of the KOR (K_i = 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%.^[1] The drug is rapidly absorbed, with maximal concentrations occurring 1 to 2 hours after administration.^[1] It has an elimination half-life of 30 to 40 hours in healthy subjects.^[1] The circulating levels of aticaprant increase proportionally with increasing doses.^[1] Steady-state concentrations are reached after 6 to 8 days of once-daily dosing.^[1] 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.^[2] 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.^[2] However, development for these indications was discontinued.^[2]

See also

κ-Opioid receptor § Antagonists

• List of investigational antidepressants

SCHEME

SYNTHESIS

WO/2024/178082COMPOSITION OF OPIOID RECEPTOR MODULATOR AND MDMA FOR USE THEREOF

WO/2024/173843QUINOLINE DERIVATIVES WHICH ACT AS KAPPA-OPIOID RECEPTOR ANTAGONISTS

20240238245COMPOSITIONS AND METHODS FOR THE TREATMENT OF DEPRESSION

20240189274Compositions And Methods For The Treatment Of Depression

WO/2024/102802ZELATRIAZIN FOR THE TREATMENT OF DEPRESSION

WO/2024/100285TREATMENT OF A COGNITIVE DISORDER WITH AN AGENT THAT INCREASES THE..

117615757Compositions and methods for treating depression

117142999Racemization method of drug intermediate

20230348377PURE FORMS OF CRYSTALLINE ATICAPRANT

WO/2023/170550POLYMORPH FORMS OF ATICAPRANT FOR USE IN TREATING MAJOR DEPRESSIVE DISORDER

WO/2023/170547PURE FORMS OF CRYSTALLINE ATICAPRANT

20230277499Forms of aticaprant

20230277500COMPOSITIONS COMPRISING ATICAPRANT

WO/2023/164385NEUROACTIVE STEROIDS FOR TREATMENT OF GASTROINTESTINAL DISEASES OR CONDITIONS

20090186873Kappa selective opioid receptor antagonist

WO/2009/094260KAPPA SELECTIVE OPIOID RECEPTOR ANTAGONIST

20100197669Kappa selective opioid receptor antagonist

2252581KAPPA SELECTIVE OPIOID RECEPTOR ANTAGONIST

201500053151-substituted 4-arylpiperazine as kappa opioid receptor antagonists

WO/2013/0864961-SUBSTITUTED 4-ARYLPIPERAZINE AS KAPPA OPIOID RECEPTOR ANTAGONISTS

101925576Kappa selective opioid receptor antagonist

PAPERS

ACS Omega (2020), 5(41), 26938-26945 https://pubs.acs.org/doi/full/10.1021/acsomega.0c04329

REF https://pubs.acs.org/doi/suppl/10.1021/acsomega.0c04329/suppl_file/ao0c04329_si_001.pdf

N-Methoxy-N-methyl-4-chlorobutyramide (S1). To a mixture of N,O-dimethylhydroxylamine hydrochloride (95.0 mmol, 9.27 g) in CH2Cl2 (150 mL) was
added 2 M NaOH (300 mmol, 150 mL) and 4-chlorobutyryl chloride (100 mmol,
11.2 mL) at 0 ˚C. The mixture was stirred for 42 h at room temperature. The
organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phase was washed with 2 M NaOH (100 mL), dried over Na2SO4, filtered, and concentrated
to afford the title comlund in 75% yield as a colorless liquid.
1H NMR (400 MHz, CDCl3) : 2.08-2.15
(m, 2H), 2.63 (t, J = 7.0 Hz, 2H), 3.19 (s, 3H), 3.64 (t, J = 6.3 Hz, 2H), 3.71 (s, 3H).
13C{
1H} NMR (100
MHz, CDCl3) : 27.1, 28.6, 32.1, 44.6, 61.1. IR (max/cm-1
): 2965, 2940, 2821, 1656, 14421, 1417, 1387,
1178, 1107, 997. HRMS (ESI+): calculated for [M+Na]+
: 188.0449, found: 188.0450.

4-Chloro-1-(3,5-dimethylphenyl)butan-1-one (S2). To a mixture of N-methoxy-N-methyl-4-chlorobutyramide (S1, 65.0 mmol, 10.8 g) in anhydrous Et2O
(100 mL) was added dropwise 3,5-dimethylphenylmagnesium bromide (ca. 1 M
in Et2O, ca. 130 mmol, prepared from 1-bromo-3,5-dimethylbenzene (130 mmol,
17.7 mL) and Mg turnings (169 mmol, 4.11 g) in anhydrous Et2O (130 mL)) over 1 h at -40 ˚C under Ar.
The reaction mixture was stirred at room temperature for 20 h. After cooling to 0 ˚C, saturated NH4Cl
solution (200 mL) was added. The organic phase was separated, washed with water (100 mL) and brine
(100 mL), dried over Na2SO4, and filtered. After concentration, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent) to afford the title compound in 91% yield as a greenish
yellow liquid.
1H NMR (400 MHz, CDCl3) : 2.18-2.25 (m, 2H), 2.38 (s, 6H), 3.15 (t, J = 7.0 Hz, 2H),
3.67 (t, J = 6.3 Hz, 2H), 7.21 (s, 1H), 7.58 (s, 2H). 13C{
1H} NMR (100 MHz, CDCl3) : 21.2, 26.8, 35.4,
44.7, 125.8, 134.8, 136.8, 138.3, 199.4. IR (max/cm-1
): 3047, 3006, 2961, 2920, 2868, 1443, 1411, 1322,
1303, 1181, 1159, 844, 785, 687. HRMS (APCI+): calculated for [M+H]+
: 211.0884, found: 211.0884.

(RS)-N-(4-Chloro-1-(3,5-dimethylphenyl)butylidene)-tertbutanesulfinamide (S3). Ti(OEt)4 (100 mol, 21.0 mL) was added to a mixture
of (RS)-tert-butanesulfinamide (1.0 M in THF, 50 mmol, 50 mL) and 4-chloro1-(3,5-dimethylphenyl)butan-1-one (S2, 50.0 mmol, 10.5 g) under N2. The mixture was refluxed for 48 h. After cooling to room temperature, brine (100 mL)
was added, and the resulting mixture was filtered over Celite using EtOAc (ca.
300 mL). The organic was separated, dried over Na2SO4, and filtered. After concentration under reduced
pressure, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent) to
afford the title compound in 57% yield as a brown viscous liquid.
1H NMR (400 MHz, CDCl3) : 1.33
(s, 9H), 2.10-2.22 (m, 2H), 2.36 (s, 6H), 3.27 (s, 1H), 3.43 (s, 1H), 3.64 (t, J = 6.5 Hz, 2H), 7.13 (s, 1H),
7.47 (s, 2H).
13C{
1H} NMR (100 MHz, CDCl3) : 21.3, 22.7, 30.2, 31.6, 44.7, 57.7, 125.2, 133.4, 137.6,
138.2, 178.6. IR (max/cm-1
): 3046, 2958, 2922, 2866, 1599, 1577, 1455, 1361, 1320, 1308, 1069, 856.
HRMS (ESI+): calculated for [M+H]
+
: 314.1340, found: 314.1344. []D
20 +11.0 (c = 1.01, CH2Cl2).

(RS,S)-1-tert-Butylsulfinyl-2-(3,5-dimethylphenyl)pyrrolidine (S4). To a solution of (RS)-N-(4-chloro-1-(3,5-dimethylphenyl)butylidene)-tert-butanesulfinamide
(S3, 25.6 mmol, 8.06 g) in anhydrous THF (100 mL) at -78 °C was added LiBEt3H
(28 mmol, 0.5 M in THF, 28.2 mL) under Ar. The reaction was stirred at -78 °C for
1 h, subsequently allowed to warm up to room temperature and stirred for additional
20 h. Saturated NaHCO3 solution (80 mL) was slowly added. The mixture was filtered and extracted
with EtOAc (3 × 100 mL). The combined organic phase was dried over Na2SO4 and filtered. After
concentration, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent)
to afford the title compound in 72% yield as pale yellow solid. mp.: 56 ˚C. 1H NMR (400 MHz, CDCl3)
: 1.12 (s, 9H), 1.74-1.90 (m, 3H), 1.93-2.02 (m, 1H), 2.18-2.27 (m, 1H), 2.30 (s, 6H), 2.94-3.02 (m, 1H),
3.85-3.91 (m, 1H), 4.55-4.59 (m, 1H), 6.88 (s, 1H), 6.90 (s, 2H).
13C{
1H} NMR (100 MHz, CDCl3) :
21.3, 23.8, 26.3, 36.0, 42.1, 57.2, 69.2, 125.0, 128.7, 137.7, 143.2. IR (max/cm-1
): 3023, 2957, 2920,
2866, 1607, 1471, 1360, 1061, 957, 847. HRMS (ESI+): calculated for [M+Na]+
: 302.1549, found:
302.1548. []D
20
-137 (c = 0.49, CH2Cl2)

(S)-2-(3,5-Dimethylphenyl)pyrrolidine hydrochloride (1j•HCl). To a solution
of (RS,S)-1-tert-butylsulfinyl-2-(3,5-dimethylphenyl)pyrrolidine (S4, 14.7 mmol,
4.12 g) in dioxane (250 mL) was added dropwise HCl (ca. 150 mmol, 4 M in dioxane, 38 mL). The mixture was stirred for 1 h at room temperature under N2, and
then the mixture was concentrated under reduced pressure. Then, Et2O (200 mL) was added to the residue
and the mixture was cooled to 0 ˚C. The precipitate was collected by filtration, washed with Et2O (40
mL), and dried under reduced pressure to afford the title compound in 94% yield as white solid. mp.: 198
˚C. 1H NMR (400 MHz, D2O) : 2.00-2.15 (m, 3H), 2.18 (s, 6H), 2.27-2.35 (m, 1H), 3.27-3.36 (m, 2H),
4.45 (t, J = 8.0 Hz, 1H), 6.97 (s, 2H), 7.01 (s, 1H). 13C{
1H} NMR (100 MHz, D2O) : 20.9, 24.19, 30.9,
46.0, 63.8, 119.79, 125.6, 131.4, 135.3, 140.1. IR (max/cm-1
): 3033, 3012, 2970, 2855, 2743, 2571, 2480,
1608, 1590, 1414, 850. HRMS (ESI+): calculated for [M-Cl]
+
: 176.1434, found: 176.1435. []D
20 +7.1
(c = 1.01, MeOH).

(S)-2-(3,5-Dimethylphenyl)pyrrolidine (1j). To a suspension of (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride (1j•HCl, 13.5 mmol, 2.86 g) in anhydrous Et2O
(200 mL) was added a saturated solution of NaHCO3 (200 mL). The resulting mixture
was stirred for 20 min at room temperature. The organic was separated and the aqueous
phase was extracted with Et2O (2 × 100 mL). The combined organic phase was dried over MgSO4 and
filtered. The solvent was removed under reduced pressure to afford the title compound as a pale yellow
liquid in 99% yield.
1H NMR (400 MHz, CDCl3) : 1.60-1.71 (m, 1H), 1.78-1.96 (m, 2H), 1.98 (s, 1H),
2.11-2.19 (m, 1H), 2.30 (s, 6H), 2.95-3.02 (m, 1H), 3.17-3.23 (m, 1H), 4.03 (t, J = 7.7 Hz, 1H), 6.87 (s,
1H), 6.97 (s, 2H). 13C{
1H} NMR (100 MHz, CDCl3) : 21.3, 25.5, 34.2, 46.9, 62.6, 124.2, 128.4, 137.8,
144.7. IR (max/cm-1
): 3332, 3010, 2960, 2915, 2869, 1605, 1458, 1101, 845. HRMS (ESI+): calculated
for [M+H]+
: 176.1434, found: 176.1436. []D
20
-30.5 (c = 1.01, MeOH). Chiral HPLC (ChiralPak ODH,  4.6 mm × L 250 mm, hexane:2-propanol = 90:10, 0.5 mL/min,  = 254 nm): tR/min = 18.7 (1%),
19.8 (99%).

3-Fluoro-4-(4-formylphenoxy)benzonitrile2
(S5). A mixture of 3,4-
difluorobenzonitrile (35.0 mmol, 4.87 g), 4-hydroxybenzaldehyde (35.0
mmol, 4.27 g), and K2CO3 (70.0 mmol, 9.67 g) in N,N-dimethylacetamide
(90 mL) was stirred at 100 ˚C for 2 h under N2. After cooling, the reaction
mixture was poured into ice water. White precipitate was collected by filtration, washed with water, and dried under reduced pressure to afford the title compound as pale yellow
solid in 82% yield. mp.: 101 ˚C. 1H NMR (400 MHz, CDCl3) : 7.11-7.15 (m, 2H), 7.20 (t, J = 8.2 Hz,
1H), 7.49-7.51 (m, 1H), 7.54 (dd, J = 9.7, 1.9 Hz, 1H), 7.91-7.94 (m, 2H), 9.98 (s, 1H).
13C{
1H} NMR
(100 MHz, CDCl3) : 109.1 (d, 3
JC-F = 8.2 Hz), 117.1 (d, 4
JC-F = 2.5 Hz), 117.9, 121.3 (d, 2
JC-F = 21.3 Hz),
122.5 (d, 4
JC-F = 1.6 Hz), 129.6 (d, 3
JC-F = 4.1 Hz), 132.1, 132.7, 147.0 (d, 2
JC-F = 11.5 Hz), 153.6 (d, 1
JCF = 254.8 Hz), 160.7, 190.4. IR (max/cm-1
): 3100, 3060, 2846, 2812, 2761, 2232, 1697, 1687, 1585, 1497,
1277, 1216, 1166, 1114, 836. HRMS (APCI+): calculated for [M+H]+
: 242.0612, found: 242.0616.

3-Fluoro-4-(4-formylphenoxy)benzamide2
(2f). To a mixture of 3-
fluoro-4-(4-formylphenoxy)benzonitrile (S5, 26.0 mmol, 6.27 g) and
K2CO3 (13.0 mmol, 1.80 g) in DMSO (24 mL) was added dropwise 35%
H2O2 (ca. 29 mmol, 3.1 mL) at 10 ˚C over 5 min. The reaction mixture
was stirred at room temperature for 2 h. The reaction mixture was
poured into ice water. White precipitate was collected by filtration, washed with water, and dried under
reduced pressure to afford the title compound as white solid in 92% yield. mp. 129 ˚C. 1H NMR (400
MHz, (D3C)2SO) : 9.96 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.93 (dd, J = 1.9, 10.0 Hz, 1H),

7.85-7.82 (m, 1H), 7.58 (s, 1H), 7.42 (t, J = 8.2 Hz, 1 H), 7.20 (d, J = 8.2 Hz, 2H).
13C{
1H} NMR (100
MHz, (D3C)2SO) : 116.6 (d, 2
JC-F = 19.7 Hz), 116.9, 122.6, 125.1 (d, 4
JC-F = 3.3 Hz), 131.9 (d, 2
JC-F =
21.3 Hz), 132.1, 132.7 (d, 3
JC-F = 5.7 Hz), 143.7 (d, 3
JC-F = 12.3 Hz), 153.1 (d, 1
JC-F = 248.2 Hz), 161.3,
165.8, 191.5. IR (max/cm-1
): 3356, 3185, 2844, 1668, 1598, 1504, 1433, 1382, 1269, 1218, 1156, 1128,

830. HRMS (ESI+): calculated for [M+Na]
     +
     : 282.0537, found: 282.0541. HRMS (APCI+): calculated
     for [M+H]+
     : 260.0717, found: 260.0716.

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Reaction Chemistry & Engineering (2022), 7(8), 1779-1785

Journal of Medicinal Chemistry (2011), 54(23), 8000-8012

References

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Further reading

• Carlezon WA, Krystal AD (October 2016). “Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials”. Depression and Anxiety. 33 (10): 895–906. doi:10.1002/da.22500. PMC 5288841. PMID 27699938.
• Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, et al. (2016). “Major Depressive Disorder and Kappa Opioid Receptor Antagonists”. Translational Perioperative and Pain Medicine. 1 (2): 4–16. PMC 4871611. PMID 27213169.
• Dhir A (January 2017). “Investigational drugs for treating major depressive disorder”. Expert Opinion on Investigational Drugs. 26 (1): 9–24. doi:10.1080/13543784.2017.1267727. PMID 27960559. S2CID 45232796.
• Reed B, Butelman ER, Kreek MJ (2017). “Endogenous opioid system in addiction and addiction-related behaviors”. Current Opinion in Behavioral Sciences. 13: 196–202. doi:10.1016/j.cobeha.2016.12.002. ISSN 2352-1546. S2CID 53149180.
• Rakesh G, Pae CU, Masand PS (August 2017). “Beyond serotonin: newer antidepressants in the future”. Expert Review of Neurotherapeutics. 17 (8): 777–790. doi:10.1080/14737175.2017.1341310. PMID 28598698. S2CID 205823807.
• Helal MA, Habib ES, Chittiboyina AG (December 2017). “Selective kappa opioid antagonists for treatment of addiction, are we there yet?”. European Journal of Medicinal Chemistry. 141: 632–647. doi:10.1016/j.ejmech.2017.10.012. PMID 29107424.
• McHugh KL, Kelly JP (2018). “Modulation of the central opioid system as an antidepressant target in rodent models”. The Opioid System as the Interface between the Brain’s Cognitive and Motivational Systems. Progress in Brain Research. Vol. 239. pp. 49–87. doi:10.1016/bs.pbr.2018.07.003. ISBN 9780444641670. PMID 30314569.
• Bailey SJ, Husbands SM (June 2018). “Targeting opioid receptor signaling in depression: do we need selective κ opioid receptor antagonists?”. Neuronal Signaling. 2 (2): NS20170145. doi:10.1042/NS20170145. PMC 7373229. PMID 32714584.
• Chavkin C (August 2018). “Kappa-opioid antagonists as stress resilience medications for the treatment of alcohol use disorders”. Neuropsychopharmacology. 43 (9): 1803–1804. doi:10.1038/s41386-018-0046-4. PMC 6046055. PMID 29752444.
• Krystal AD, Pizzagalli DA, Mathew SJ, Sanacora G, Keefe R, Song A, et al. (December 2018). “The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development”. Nature Reviews. Drug Discovery. 18 (1): 82–84. doi:10.1038/nrd.2018.222. PMC 6816017. PMID 30591715.
• Lazar MA, McIntyre RS (2019). “Novel Therapeutic Targets for Major Depressive Disorder”. Neurobiology of Depression. pp. 383–400. doi:10.1016/B978-0-12-813333-0.00034-2. ISBN 9780128133330. S2CID 86782597.
• Browne CA, Lucki I (September 2019). “Targeting opioid dysregulation in depression for the development of novel therapeutics”. Pharmacology & Therapeutics. 201: 51–76. doi:10.1016/j.pharmthera.2019.04.009. PMC 6859062. PMID 31051197.
• Banks ML (2020). “The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research”. In Nader MA, Hurd YL (eds.). Substance Use Disorders. Handbook of Experimental Pharmacology. Vol. 258. pp. 147–165. doi:10.1007/164_2019_268. ISBN 978-3-030-33678-3. PMC 7756963. PMID 31463605.
• Browne CA, Jacobson ML, Lucki I (2020). “Novel Targets to Treat Depression: Opioid-Based Therapeutics”. Harvard Review of Psychiatry. 28 (1): 40–59. doi:10.1097/HRP.0000000000000242. PMID 31913981. S2CID 210120636.
• Jacobson ML, Browne CA, Lucki I (January 2020). “Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders”. Annual Review of Pharmacology and Toxicology. 60: 615–636. doi:10.1146/annurev-pharmtox-010919-023317. PMID 31914893. S2CID 210121357.
• Mercadante S, Romualdi P (2020). “The Therapeutic Potential of Novel Kappa Opioid Receptor-based Treatments”. Current Medicinal Chemistry. 27 (12): 2012–2020. doi:10.2174/0929867326666190121142459. PMID 30666905. S2CID 58558833.

External links

Aticaprant – Eli Lilly and Company/Janssen Pharmaceuticals – AdisInsight

//////ATICAPRANT, CERC-501, JSPA 0658, JSPA-0658, JSPA0658, LY 2456302, LY-2456302, LY2456302, Phase 3, ELI LILLY, Major depressive disorder, JNJ-67953964, WHO 10582