| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt). Izumerogant (IMU-935) is a novel inverse agonist of RORγt. [1]
In a reporter assay, IMU-935 showed an IC₅₀ of approximately 20 nM. The compound also inhibits dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine synthesis. [1] |
|---|---|
| ln Vitro |
In stimulated human lymphocytes, IMU-935 inhibited the release of IL-17A, IL-17F, and interferon-γ cytokines, with IC₅₀ values in the low-single-digit nanomolar range (3-5 nM). [1]
In vitro metabolism studies showed that IMU-935 is mainly metabolized by CYP3A4 (approximately 90%) and to a lesser extent by CYP1A2 (approximately 10%). In liver microsome studies, 26 metabolites were observed across different species, of which 10 were detected in humans, predominantly consisting of an O-dealkylation metabolite, a hydroxylation metabolite in the methylbutanol moiety, and a glucuronide-conjugated metabolite. [1] Plasma protein binding of IMU-935 was high in animals and humans, with fraction unbound < 2%. [1] In in vitro interaction studies, IMU-935 inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4, with IC₅₀ values ranging from 6 μM (CYP2C9) to 19 μM (CYP2B6). [1] |
| ln Vivo |
The retinoic acid receptor-related orphan nuclear receptor γt (RORγt) controls the transcription of interleukin-17 and other cytokines involved in inflammatory and autoimmune conditions. In this first-in-human phase 1 study, we evaluated the safety, tolerability, and pharmacokinetics of IMU-935, an inverse agonist of RORγt. The trial was double-blind and placebo-controlled, with healthy participants randomly assigned to receive either single ascending doses (25–400 mg) or multiple ascending doses (150 mg once or twice daily for 14 days) of IMU-935 or matching placebo. Dose escalation decisions were guided by safety, tolerability, and PK assessments. A total of 24 subjects received placebo and 70 received IMU-935; among those given IMU-935, 59 received a single dose and 11 received multiple doses. Treatment-emergent adverse events occurred in 21 subjects (88%) on placebo and 58 (83%) on IMU-935. Treatment-related TEAEs were reported in 6 subjects (30%) after a single placebo dose and in 25 (42%) after a single IMU-935 dose. With the exception of two moderate events in the IMU-935 group and one moderate event in the placebo group, all treatment-related TEAEs were mild. No treatment-related discontinuations or serious adverse events occurred. The PK of IMU-935 was dose-proportional, with an approximate half-life of 24 hours. In summary, IMU-935 was safe, exhibited no dose-limiting toxicities, and demonstrated a PK profile suitable for once-daily dosing.
|
| Enzyme Assay |
No detailed enzyme assay methodology is described in this article. The IC₅₀ values for RORγt inhibition (approx. 20 nM in a reporter assay) and for cytokine release (3-5 nM) are reported from preclinical data on file. [1]
|
| Cell Assay |
No detailed enzyme assay methodology is described in this article. The IC₅₀ values for RORγt inhibition (approx. 20 nM in a reporter assay) and for cytokine release (3-5 nM) are reported from preclinical data on file. [1]
|
| Animal Protocol |
. This was a first-in-human clinical trial. [1]
|
| ADME/Pharmacokinetics |
IMU-935 was readily absorbed after oral administration, with a median tₘₐₓ between 2.00 and 3.53 hours, followed by a biphasic elimination phase. The PK of IMU-935 were dose proportional between single doses of 100 and 400 mg. The half-life was approximately 24 hours and generally consistent across doses. [1]
After a single 300 mg dose of IMU-935 (powder formulation), the geometric least squares mean ratio between fed and fasted states for Cₘₐₓ was 30.5% (90% CI: 10.4%-89.7%), and for AUC₀-inf was 56.7% (90% CI: 23.0%-140%), indicating a significant food effect that decreased exposure and Cₘₐₓ. [1] Less than 0.01% of IMU-935 was excreted unchanged in urine, with no quantifiable excretion on days 2 and 3. [1] Following once-daily dosing of 150 mg, steady-state concentrations were achieved after 4 days of daily dosing, and plasma trough levels remained stable until the end of treatment. The geometric mean accumulation ratios (Day 14/Day 1) for Cₘₐₓ and AUC₀-τ were 0.73 (CV% 115%) and 1.23 (CV% 59%), respectively, for once-daily dosing, and 1.24 (CV% 37%) and 2.02 (CV% 16%), respectively, for twice-daily dosing. [1] |
| Toxicity/Toxicokinetics |
IMU-935 was safe with no dose-limiting toxicities in healthy subjects at single doses up to 400 mg and multiple doses of 150 mg once or twice daily for 14 days. [1]
Treatment-emergent adverse events (TEAEs) occurred in 58/70 subjects (83%) given any dose of IMU-935 and 21/24 subjects (88%) given placebo. Most TEAEs were mild in severity. No serious adverse events, TEAEs leading to study discontinuation, or deaths occurred. [1] The most common TEAEs in subjects receiving a single dose of IMU-935 were headache (22%), diarrhea (14%), catheter site pain (10%), nausea (8%), fatigue (7%), abdominal distention (7%), and dizziness (7%). Diarrhea occurred more frequently with the lipid-based formulation (17%) than with the powder formulation (3%). In subjects receiving multiple doses of IMU-935, TEAEs occurring in >1 subject consisted of headache (45%), back pain (18%), and epistaxis (18%). [1] Treatment-related TEAEs occurred in 25/59 subjects (42%) given a single dose of IMU-935 and 7/11 subjects (64%) given multiple doses of IMU-935. All treatment-related TEAEs were mild except for 2 moderate events (flushing and headache) in the single-dose IMU-935 group and 1 moderate event (constipation) in the placebo group. [1] A maximum tolerated dose was not established in either the single- or multiple-dose cohorts. [1] Four subjects experienced TEAEs related to clinical laboratory parameters or electrocardiograms (3 receiving IMU-935, 1 receiving placebo), consisting of increased transaminases, increased lipase, PR prolongation, and leukocyturia. All events were not clinically relevant, were considered unrelated to the study drug, and resolved within 30 days. [1] |
| References |
|
| Additional Infomation |
Izumerogant (IMU-935) is a novel inverse agonist of RORγt being developed for the treatment of inflammatory and autoimmune diseases, including plaque psoriasis. [1]
The compound has a dual mechanism of action: it inhibits RORγt (IC₅₀ ≈ 20 nM in a reporter assay) and also inhibits dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine synthesis in proliferating T lymphocytes. This dual mechanism may prove more efficacious against immune-mediated conditions than either mechanism alone. [1] Preclinical studies indicate that IMU-935 does not affect thymocyte maturation because basal RORγt activity is maintained. This is relevant because complete abrogation of RORγt function has been associated with thymic lymphomas in animal models. [1] |
| Molecular Formula |
C22H18CLF4N5O2
|
|---|---|
| Molecular Weight |
495.86
|
| Exact Mass |
495.108
|
| Elemental Analysis |
C, 53.29; H, 3.66; Cl, 7.15; F, 15.33; N, 14.12; O, 6.45
|
| CAS # |
2299252-72-3
|
| PubChem CID |
154695807
|
| Appearance |
Off-white to light brown solid powder
|
| LogP |
3.8
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
34
|
| Complexity |
684
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC(C)(CCN1C(=C(C=N1)C2=C(C(=NO2)C3=C(C=CC=C3Cl)F)C4=NC=CC=N4)C(F)(F)F)O
|
| InChi Key |
MRJLIFZIFUEXQG-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C22H18ClF4N5O2/c1-21(2,33)7-10-32-19(22(25,26)27)12(11-30-32)18-16(20-28-8-4-9-29-20)17(31-34-18)15-13(23)5-3-6-14(15)24/h3-6,8-9,11,33H,7,10H2,1-2H3
|
| Chemical Name |
4-[4-[3-(2-chloro-6-fluorophenyl)-4-pyrimidin-2-yl-1,2-oxazol-5-yl]-5-(trifluoromethyl)pyrazol-1-yl]-2-methylbutan-2-ol
|
| Synonyms |
Izumerogant; IMU-935; IMU935; 2299252-72-3; IMU 935; izumerogant [INN]; 3YCU39T8ZJ;
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| 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
|
|---|---|
| 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 | 2.0167 mL | 10.0835 mL | 20.1670 mL | |
| 5 mM | 0.4033 mL | 2.0167 mL | 4.0334 mL | |
| 10 mM | 0.2017 mL | 1.0083 mL | 2.0167 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.
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