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Purity: ≥98%
Indiplon (NBI-34060; CL-285,489) is a nonbenzodiazepine class of hypnotic sedative which works by enhancing the action of the inhibitory neurotransmitter GABA, like most other nonbenzodiazepine sedatives. It primarily binds to the α1 subunits of the GABAA receptors in the brain. Indiplon was approved for the treatment of insomnia. Like other non-benzodiazepine hypnotics, its mechanism of action is to modulate subunits, especially the alpha-1 subunit, of the GABA receptor complex in order to induce sedation. Indiplon was developed in two different formulations to address two different types of indiplon-IR (immediate release) was designed for sleep onset difficulties, while indiplon-MR (modified release) was developed for sleep maintenance insomnia. While there are currently few peer reviewed articles about indiplon clinical trial results, the early information that is available seems to indicate that both formulations have been well tolerated and have proven effective at improving both patient reported and objectively measured sleep parameters in both adult and elderly insomnia patients. In May 2006, the FDA indicated that indiplon-IR was approvable and plans are to resubmit the application in 2007. Indiplon-MR was unapprovable and may require further evaluation.
| Targets |
GABAA receptors . [1]
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|---|---|
| Enzyme Assay |
Indiplon hydrolase activity was determined by incubating various enzyme sources (human liver microsomes, human liver cytosol, human plasma, or homogenates of insect cells expressing recombinant AADAC, CES1, or CES2) in 100 mM potassium phosphate buffer (pH 7.4) containing 50 μM indiplon (final DMSO concentration 1%). After a 2‑min preincubation at 37°C, the reaction was initiated by adding indiplon and incubated for 30 min at 37°C. The reaction was terminated by adding ice‑cold acetonitrile. The mixture was centrifuged to remove protein, and the supernatant was analyzed by HPLC using a reversed‑phase column (Symmetry Shield RP8) with a mobile phase of 23% acetonitrile containing 0.1% trifluoroacetic acid at a flow rate of 1.0 mL/min, and the eluent was monitored at 230 nm. [1]
LC‑MS/MS analysis was performed to identify the hydrolyzed metabolite. The LC system used an Inertsil ODS‑3 column with a mobile phase gradient of 0.1% trifluoroacetic acid (A) and acetonitrile with 0.1% trifluoroacetic acid (B): 20% B (0‑10 min), 20‑25% B (10‑11 min), 25% B (11‑30 min) at a flow rate of 0.2 mL/min. Mass spectrometry was operated in positive electrospray ionization mode. Full‑scan spectra (Q1 scan, m/z 80‑400) and multiple‑reaction monitoring (MRM) transitions (m/z 377.1→293.2 for indiplon and m/z 335.1→251.2 for deacetylindiplon) were recorded. [1] Kinetic analysis was performed using human liver microsomes and recombinant AADAC with substrate concentrations ranging from 20 to 500 μM. The data were fitted to the Michaelis‑Menten equation using nonlinear regression analysis. For human liver microsomes, the Km was 179 ± 6.5 μM and Vmax was 532 ± 16.0 pmol/min/mg. For recombinant AADAC, the Km was 45.4 ± 2.3 μM and Vmax was 374 ± 7.8 pmol/min/mg. [1] Inhibition studies were carried out using various inhibitors: BNPP (100 μM), DFP (100 μM), PMSF (100 μM), eserine (100 μM), vinblastine (50 μM), digitonin (200 μM), telmisartan (5 μM), and loperamide (5 μM). The inhibitors were preincubated with the enzyme source before adding indiplon, and the residual hydrolase activity was measured as described above. [1] |
| ADME/Pharmacokinetics |
Metabolism / Metabolites
Indiplon's known human metabolites include N-demethylindiplon. In human liver microsomes, indiplon is hydrolyzed to N‑deacetylindiplon, accounting for approximately 30‑40% of the overall in vitro clearance, while N‑demethylation by CYP3A4/5 accounts for 60‑70%. [1] Kinetic parameters for indiplon hydrolysis in human liver microsomes: Km = 179 ± 6.5 μM, Vmax = 532 ± 16.0 pmol/min/mg, intrinsic clearance (Clint) = 3.0 ± 0.1 μL/min/mg. For recombinant human AADAC: Km = 45.4 ± 2.3 μM, Vmax = 374 ± 7.8 pmol/min/mg, Clint = 8.3 ± 0.3 μL/min/mg. [1] Indiplon hydrolase activity in human liver cytosol was markedly lower (9.4 ± 0.8 pmol/min/mg at 50 μM) than in human liver microsomes (228.0 ± 2.2 pmol/min/mg at 50 μM), and no detectable activity was found in human plasma. [1] |
| References |
: Shimizu M, Fukami T, Ito Y, Kurokawa T, Kariya M, Nakajima M, Yokoi T. Indiplon is hydrolyzed by arylacetamide deacetylase in human liver. Drug Metab Dispos. 2014 Apr;42(4):751-8.
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| Additional Infomation |
Indiplon belongs to the pyrimidine class of drugs. Indiplon has been used in clinical trials for the treatment of insomnia and depression.
Indiplon was initially developed as a hypnotic sedative drug, but its development was discontinued due to the company's circumstances. [1] The hydrolysis of indiplon in humans is primarily catalyzed by arylacetamide deacetylase (AADAC), which preferentially cleaves the acetyl group. [1] Human AADAC genetic polymorphisms exist: AADAC2 (c.841G>A, leading to V281I substitution) and AADAC3 (c.841G>A and c.1288T>C, leading to V281I and Q400X truncation). The AADAC.3 variant exhibits markedly decreased indiplon hydrolase activity. [1] In a panel of 24 individual human liver microsome samples, indiplon hydrolase activity varied 8.5‑fold (range 16.8 to 143.4 pmol/min/mg). The sample homozygous for the AADAC3 allele showed the lowest activity among the tested samples. [1] |
| Molecular Formula |
C20H16N4O2S
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|---|---|
| Molecular Weight |
376.43
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| Exact Mass |
376.099
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| CAS # |
325715-02-4
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| Related CAS # |
325715-02-4;
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| PubChem CID |
6450813
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.700
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| LogP |
0.83
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
574
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(=O)N(C)C1=CC=CC(=C1)C2=CC=NC3=C(C=NN23)C(=O)C4=CC=CS4
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| InChi Key |
CBIAWPMZSFFRGN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H16N4O2S/c1-13(25)23(2)15-6-3-5-14(11-15)17-8-9-21-20-16(12-22-24(17)20)19(26)18-7-4-10-27-18/h3-12H,1-2H3
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| Chemical Name |
N-methyl-N-[3-[3-(thiophene-2-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]acetamide
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| Synonyms |
NBI-34060 NBI34060 NBI 34060 CL285,489 CL-285,489 CL 285,489 CL-285489 CL 285489 CL285489 Indiplon
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6565 mL | 13.2827 mL | 26.5654 mL | |
| 5 mM | 0.5313 mL | 2.6565 mL | 5.3131 mL | |
| 10 mM | 0.2657 mL | 1.3283 mL | 2.6565 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00232167 | Terminated | Drug: Indiplon Drug: Sertraline |
Depression Insomnia |
Neurocrine Biosciences | 2005-11 | Phase 3 |
| NCT00525941 | Withdrawn | Drug: NBI-34060 | Insomnia | Neurocrine Biosciences | 2007-09 | Phase 3 |
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