JNJ-42847922 is a high-affinity, potent, and selective orexin-2 receptor (OX2R) antagonist. It has an approximate 2-log selectivity ratio versus the human orexin-1 receptor (OX1R). Binding affinity (pKi) for human OX2R is 8.0 ± 0.1, and for rat OX2R is 8.1 ± 0.1. Binding affinity (pKi) for human OX1R is 6.1 ± 0.2, and for rat OX1R is 6.2 ± 0.1. Functional antagonism potency (pKb) for human OX2R is 8.8 ± 0.2, and for rat OX2R is 8.0 ± 0.1. Functional antagonism potency (pKb) for human OX1R is 6.3 ± 0.3, and for rat OX1R is <6.0 ± 0.01 [1].

In radioligand binding assays, JNJ-42847922 demonstrated high-affinity binding to both human and rat OX2R. In a panel of 50 receptors, ion channels, and transporter assays, JNJ-42847922 at 1 μM showed no significant affinity ( < 50% inhibition) for any target other than OX2R, indicating high selectivity. In calcium mobilization functional assays, JNJ-42847922 acted as a potent antagonist, with its pKb values correlating well with its pKi values for both human and rat OX2R [1].

In rats, oral administration of JNJ-42847922 (3-30 mg/kg) during the light phase dose-dependently reduced the latency to non-rapid eye movement (NREM) sleep and prolonged NREM sleep time in the first 2 hours, with minimal effects on REM sleep. Sleep consolidation was enhanced, as indicated by a prolonged NREM bout duration. The sleep-promoting effects were maintained upon 7-day repeated dosing (30 mg/kg/day) without evidence of rebound upon discontinuation. JNJ-42847922 (30 mg/kg, p.o.) promoted sleep in wild-type mice but had no effect on sleep parameters in OX2R knockout mice, confirming the specific OX2R-mediated mechanism of action. The compound (30 mg/kg, p.o.) did not increase dopamine release in the rat nucleus accumbens, nor did it produce conditioned place preference in mice (10 mg/kg, i.p.), suggesting a lack of intrinsic motivational properties, unlike zolpidem. Furthermore, JNJ-42847922 (30 mg/kg, p.o.) did not affect motor coordination or exacerbate alcohol-induced ataxia in rats, in contrast to zolpidem. In a first-in-human trial, single oral doses (10-80 mg) increased somnolence in healthy subjects, with the effect appearing dose-dependent [1].

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At doses up to Sprague-Dawley weight, seltorexant (JNJ-42847922) (3–30 mg/kg; flour) initiates and prolongs sleep [1]. 30 mg/kg seltorexant (wall; daily for 7 days)

The affinity of JNJ-42847922 for human and rat orexin receptors was determined using competitive radioligand binding assays. For OX2R, cell membranes from HEK-293 cells (transfected with human OX2R) or CHO-K1 cells (transfected with rat OX2R) were incubated with 2 nM of the OX2R radioligand [³H]EMPA and various concentrations of the test compound for 60 minutes at room temperature. Nonspecific binding was defined using 10 μM almorexant. Bound radioactivity was separated by filtration and counted. For OX1R, cell membranes from CHO-K1 cells (human OX1R) or HEK-293 cells (rat OX1R) were incubated with 4 nM of the OX1R radioligand [³H]SB-674042 and the test compound. Nonspecific binding was also determined with 10 μM almorexant. Ki values were calculated from the inhibition curves [1].

The functional antagonism of JNJ-42847922 at orexin receptors was evaluated by measuring its ability to inhibit agonist-induced intracellular calcium mobilization. For human OX2R, PFSK-1 cells, which endogenously express the receptor, were used. For rat OX2R, SK-N-MC cells stably expressing the rat OX2R were used. For OX1R, stably transfected CHO-K1 (human OX1R) or HEK293 (rat OX1R) cells were employed. Cells were plated in 96-well plates and grown overnight. On the day of the assay, cells were incubated with various concentrations of JNJ-42847922 before being stimulated with an EC₈₀ concentration of an orexin receptor agonist. The resulting transient increase in intracellular calcium was measured. The potency of the antagonist (pKb) was calculated from the inhibition of the agonist response [1].

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (350-450 g) [1]
Doses: 30 mg/kg
Route of Administration: po; in the antenna The sleep-prolonging effect remains stable after 7 days of repeated spraying [1]. Once-daily for 7 days
Experimental Results: Reductions in sleep onset time (non-rapid eye movement (NREM) latency) and increases in NREM sleep duration were maintained after repeated dosing of JNJ-42847922 for 7 days. The prolongation of NREM sleep duration was due to a significant increase in NREM episode duration throughout the treatment period assessed on D1 and D7. Rapid eye movement (REM) sleep was only slightly affected on day 4 of treatment, resulting in a small but significant decrease in REM sleep latency and an increase in REM sleep duration.

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For the sleep efficacy study in rats, male Sprague-Dawley rats were orally dosed with vehicle or JNJ-42847922 (3, 10, 30 mg/kg) 2 hours into the light phase. Sleep-wake patterns were recorded for the subsequent 2 hours. For the repeated dosing study, rats were dosed orally with vehicle for 2 days, then with JNJ-42847922 (30 mg/kg/day) for 7 days, followed by vehicle for 2 days. Sleep parameters were recorded during the first 2 hours post-dose [1].
For the OX2R knockout mouse study, OX2R KO and wild-type mice were orally administered vehicle or JNJ-42847922 (30 mg/kg) at the onset of the dark phase. Sleep parameters were assessed for the following 2 hours [1].
For the microdialysis study in rats, JNJ-42847922 (30 mg/kg) was administered orally, and dopamine levels in the nucleus accumbens of freely moving rats were measured [1].
For the conditioned place preference test in mice, animals were conditioned for 4 days with intraperitoneal injections of vehicle, JNJ-42847922 (10 mg/kg), zolpidem (10 mg/kg), or amphetamine (2 mg/kg) in a biased manner. On day 6, the time spent in each chamber was recorded over 15 minutes [1].
For the rotarod test in rats, animals were trained a day prior. On the test day, they received an oral dose of JNJ-42847922 (30 mg/kg), zolpidem (10 mg/kg), or vehicle, and were tested 15 minutes later. In the alcohol interaction study, ethanol (1 g/kg, i.p.) was co-administered. The time the animals remained on the rotating drum was recorded up to a 60-second cutoff [1].
For the ex vivo receptor occupancy study in rats, animals were orally administered JNJ-42847922 (30 mg/kg for time course; 1-60 mg/kg for dose-response). At specified time points (15 min to 24 h) post-dose, brains were collected, sectioned, and incubated with [³H]EMPA to determine OX2R occupancy via autoradiography [1].

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Ex vivo receptor occupancy: Male Sprague-Dawley rats were orally administered Seltorexant (JNJ-42847922) (3-60 mg/kg). At specific time points post-dose, brains were collected, sectioned, and subjected to autoradiography using [3H]EMPA to quantify OX2R occupancy.
Sleep studies in rats: Male Sprague-Dawley rats, implanted with telemetry transmitters, were orally dosed with vehicle or Seltorexant (JNJ-42847922) (3, 10, 30 mg/kg) 2 hours into the light phase. Sleep-wake parameters were recorded and analyzed for the subsequent 2 hours. For the repeated dosing study, rats received vehicle for 2 days, then 30 mg/kg/day for 7 days, followed by vehicle for 2 recovery days.
Sleep studies in mice: OX2R knockout and wild-type mice were orally administered Seltorexant (JNJ-42847922) (30 mg/kg) at dark onset. EEG and EMG were recorded to assess sleep parameters for 2 hours post-dose.
Microdialysis: Rats with guide cannulas aimed at the nucleus accumbens were orally dosed with Seltorexant (JNJ-42847922) (30 mg/kg). Dialysate samples were collected every 30 minutes and analyzed for dopamine levels by HPLC with electrochemical detection. Amphetamine (0.3 mg/kg s.c.) was used as a positive control.
Conditioned Place Preference: Mice were conditioned for 5 days, receiving vehicle or Seltorexant (JNJ-42847922) (10 mg/kg i.p.) in the morning and vehicle in the afternoon. On day 6, they were given free access to all chambers, and the time spent in each was recorded.
Rotarod test: Trained rats were orally administered vehicle, Seltorexant (JNJ-42847922) (30 mg/kg), or zolpidem (10 mg/kg), with or without ethanol (1 g/kg i.p.). The latency to fall from the rotating drum was recorded 15 minutes post-treatment, with a 60-second cutoff. [1]

In rats, after oral administration, JNJ-42847922 showed rapid brain penetration and clearance, with OX2R occupancy reaching a peak of 74 ± 6% at 60 minutes and decreasing to 40% within 4 hours. The ED₅₀ of OX2R occupancy in rats was 3 mg/kg, equivalent to a total plasma concentration of 171 ng/ml and a free plasma concentration of 9.58 ng/ml. In first-in-human single-dose escalation studies (10–80 mg), JNJ-42847922 was rapidly absorbed, with a time to peak concentration (tmax) of 0.33 to 0.5 hours. Its concentration decreased in a single phase with a terminal half-life of approximately 2 hours. Cmax and AUC both increased with increasing dose, but the increase was slightly less than that of the dose-proportional relationship [1].

JNJ-42847922 was well-tolerated in rats and dogs with single and multiple doses over a period of up to one month. It was not genotoxic in standard genotoxicity tests and was well-tolerated in canine cardiovascular safety studies. In the first-in-human trials, single doses of 10 to 80 mg were safe and well-tolerated in healthy subjects. All adverse events were mild or moderate. The most common adverse event was somnolence (85% in the active drug group, 23% in the placebo group). Other reported adverse events included headache (12%) and dizziness/orthostatic vertigo (12%). One subject who received 80 mg experienced a brief episode of sleep paralysis. No clinically significant adverse events were identified in other safety assessments [1].

[1]. Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia. J Pharmacol Exp Ther. 2015 Sep;354(3):471-82.

Dual orexin receptor antagonists have been shown to promote sleep in a variety of species, including humans. Emerging research suggests that selective orexin-2 receptor (OX2R) antagonists may provide higher specificity and more suitable sleep patterns by maintaining normal sleep structure. This article characterized the high-affinity/potency OX2R antagonist JNJ-42847922 ([5-(4,6-dimethylpyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrolo-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methyl ketone). JNJ-42847922 showed a selectivity of approximately two orders of magnitude for human orexin-1 receptors. In vitro receptor binding experiments demonstrated that, after oral administration, JNJ-42847922 rapidly occupied OX2R binding sites in the rat brain and was quickly cleared from the brain. In rats, a single oral dose of JNJ-42847922 (3–30 mg/kg) during photoperiod dose-dependently shortened non-rapid eye movement (NREM) sleep latency and prolonged the first 2 hours of NREM sleep time, with minimal effect on rapid eye movement (REM) sleep. Repeated administration of JNJ-42847922 (30 mg/kg) for 7 consecutive days maintained the effects of shortened sleep latency and prolonged sleep time, and all sleep parameters returned to baseline levels upon discontinuation of the drug. Although this compound promoted sleep in wild-type mice, it had no effect on OX2R knockout mice, consistent with OX2R-mediated sleep responses. JNJ-42847922 did not increase dopamine release in the nucleus accumbens of rats, nor did it induce positional preference in mice after subchronic conditioning, indicating a lack of intrinsic motivational properties, unlike zolpidem. In a single-dose escalation study in healthy subjects, JNJ-42847922 increased drowsiness and demonstrated good sedative-hypnotic pharmacokinetics and safety, thus showing promise as a candidate drug for the treatment of insomnia and is expected to undergo further clinical development. [1] JNJ-42847922 (also known as Seltorexant) is a selective orexin-2 receptor antagonist currently being developed as a clinical candidate drug for the treatment of insomnia. Its mechanism of action is based on pharmacological blockade of OX2R, which is sufficient to initiate and prolong sleep. Unlike dual orexin receptor antagonists (DORAs) that promote both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, the selective OX2R antagonism of JNJ-42847922 primarily promotes NREM sleep and maintains sleep structure. In preclinical models, this drug is significantly different from the non-benzodiazepine hypnotics zolpidem. It does not have a tendency to be abused, nor does it impair motor coordination or exacerbate alcohol-induced ataxia. Based on its good preclinical characteristics, this drug entered the clinical trial stage and demonstrated strong hypnotic-like effects, as well as good pharmacokinetics and safety in the clinical trial, becoming a promising new type of non-sedative hypnotics for insomnia[1].

C21H22FN7O

407.444086551666

407.187

C, 61.90; H, 5.44; F, 4.66; N, 24.06; O, 3.93

1293281-49-8

Seltorexant hydrochloride;1293284-49-7

67116280

White to yellow solid powder

2.8

0

7

3

30

609

0

FC1C=CC=C(C=1C(N1CC2CN(C3N=C(C)C=C(C)N=3)CC2C1)=O)N1N=CC=N1

SQOCEMCKYDVLMM-UHFFFAOYSA-N

InChI=1S/C21H22FN7O/c1-13-8-14(2)26-21(25-13)28-11-15-9-27(10-16(15)12-28)20(30)19-17(22)4-3-5-18(19)29-23-6-7-24-29/h3-8,15-16H,9-12H2,1-2H3

((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

MIN-202; JNJ42847922; MIN 202; JNJ-42847922; MIN202; JNJ 42847922; Seltorexant

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~61.36 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.14 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.14 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.14 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)