Retinoid-related orphan receptor γ (RORγ) [1].
Retinoic acid receptor-related orphan receptor γ (RORγ) [2].
EC₅₀: 13 nM (in RORγ luciferase reporter assay) [2].

In a RORγ luciferase reporter assay, JTE-151 demonstrated potent inhibitory activity with an EC₅₀ of 13 nM. The ligand efficiency (LE) was 0.31, and the Fsp³ value was 0.61 [2].
JTE-151 exhibited high selectivity for RORγ over other nuclear receptors. Antagonist activity against hRORα, hRORβ, and hSF1 was assessed, showing >100-fold selectivity. No agonist or antagonist activity was observed against 12 other nuclear receptors (mGR, hAR, hERα, hPR, hVDR, hFXR, mLXRα, hPPARα, hPPARδ, hPPARγ, hRARα, hRXRα) at concentrations up to 10 μM [2].
In selectivity profiling against a panel of off-target receptors and enzymes (including A₁, α₁, α₂, β₁, β₂, β₃, Ca²⁺ channel, CB₁, D₁, GABA_A, GABA_B, glutamate, H₁, H₂, H₃, K_ATP, muscarine, nicotine, opiate, 5HT₁A, 5HT₂A, 5HT₃, ACE, COX-1, MAO-A, MAO-B, and NOS), the IC₅₀ values for JTE-151 were >10 μM, with the exception of the D₁ receptor, which showed an IC₅₀ of 6.2 μM [2].
JTE-151 showed weak direct inhibition against CYP2C8 (IC₅₀ = 6.8 μM). IC₅₀ values for other typical CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5 (testosterone), CYP3A4/5 (midazolam)) were >10 μM [2].

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Mechanism of Action:
- JTE-151 binds to the human RORγ ligand-binding domain (LBD), dissociating co-activator peptides and recruiting co-repressor peptides
- It potently inhibits the transcriptional activity of RORγ in human, mouse, and rat species

Cellular Effects:
- Suppresses differentiation of mouse naïve CD4⁺ T cells into Th17 cells without affecting differentiation into other CD4⁺ T cell subsets (Th1, Th2, or Treg)
- Inhibits IL-17A and IL-22 production from antigen-stimulated (MOG peptide) Th17 cells, whereas anti-IL-12/IL-23 p40 antibody does not
- Inhibits IL-17A and IL-22 production from cytokine-stimulated (IL-23) Th17 cells
- Selectively inhibits interleukin-17 (IL-17) production from activated human helper T cells, with no effect on interferon-γ (IFN-γ) or IL-4 production

Selectivity:
- Demonstrates high selectivity against other nuclear receptor family members
- Greater than 100-fold selectivity against hRORα, hRORβ, hSF1; no agonist or antagonist activity against 12 other nuclear receptors (including GR, AR, ERα, PR, VDR, FXR, LXRα, PPARα/δ/γ, RARα, RXRα)

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MOG₃₅₋₅₅-Induced EAE Model in Mice: In a mouse model of experimental autoimmune encephalomyelitis (EAE) induced by MOG₃₅₋₅₅/CFA immunization, oral administration of JTE-151 at 3 and 10 mg/kg suppressed IL-17 levels in both lymph nodes and plasma [2].
At 10 mg/kg, JTE-151 significantly decreased the EAE clinical score (severity of paralysis) and demonstrated better efficacy compared to anti-IL-17A antibody. Treatment also reduced the number of Th17 cells in the spinal cords, indicating suppression of Th17 cell differentiation [2]. Pharmacodynamics:
- Suppresses IL-17 production in antigen-sensitized mice
- At 3 and 10 mg/kg, JTE-151 suppresses IL-17 levels in mice and reduces the number of Th17 cells in spinal cords
- At 10 mg/kg, significantly decreases experimental autoimmune encephalomyelitis (EAE) clinical scores (severity of paralysis), demonstrating better efficacy compared to anti-IL-17A antibody

Rheumatoid Arthritis Models:
- In collagen-induced arthritis (CIA) rats, both prophylactic and therapeutic treatment ameliorates hindpaw swelling, bone destruction, and inhibits mRNA expression of Th17-related genes in knee synovial tissue
- Similar inhibitory effects observed in adjuvant-induced arthritis (AIA) rats
- Co-administration with anti-TNFα antibody produces stronger arthritis symptom relief than either agent alone in CIA mice

Psoriasis Models:
- Suppresses MOG-induced ear swelling in MOG-immunized mice
- Ameliorates IL-23-induced dermatitis in mice through inhibition of Th17 cell activation

RORγ Luciferase Reporter Assay: This assay was used to evaluate RORγ inhibitory activity. HEK293 cells were transiently transfected with a reporter construct containing a luciferase gene under the control of a ROR response element and a vector expressing full-length human RORγ. After 24 hours, compounds were added and incubated for an additional 18-24 hours. Luciferase activity was measured, and EC₅₀ values were calculated from dose-response curves [2].
Nuclear Receptor Selectivity Assays: Selectivity against other nuclear receptors was assessed using commercially available reporter assay systems (e.g., GAL4-based or full-length receptor assays) according to the manufacturer’s protocols. Both agonist and antagonist activities were evaluated at compound concentrations up to 10 μM [2].

The in vitro activity was primarily characterized using the RORγ luciferase reporter assay in transfected HEK293 cells [2].

Mouse EAE Model: Female C57BL/6 mice were immunized subcutaneously with an emulsion containing MOG₃₅₋₅₅ peptide and complete Freund’s adjuvant (CFA) containing Mycobacterium tuberculosis. Pertussis toxin was administered intraperitoneally on days 0 and 2. JTE-151 was formulated in 0.5% methylcellulose as an aqueous suspension and administered orally once daily from day 1 to day 17 at doses of 3 and 10 mg/kg. Anti-IL-17A antibody (0.2 mg/mouse) was administered intraperitoneally on days 1 and 15 as a comparator. Clinical scores were assessed daily based on paralysis severity. On day 18, spinal cords were collected for mononuclear cell isolation and flow cytometric analysis of Th17 cells [2].

Mouse PK: Following intravenous administration (1 mg/kg, in DMSO) in mice, JTE-151 showed a terminal half-life (t₁/₂β) of 3.8 hours, total body clearance (CLtot) of 0.03 L/h/kg, and volume of distribution at steady state (Vdss) of 0.16 L/kg. After oral administration (3 mg/kg, as an aqueous suspension in 0.5% methylcellulose), the area under the curve (AUC) was 1735 μM·h, mean residence time (MRT) was 5.8 hours, and oral bioavailability (F) was 98% [2].
Rat PK: In rats, intravenous administration (1 mg/kg, in DMSO) gave t₁/₂β of 3.0 hours, CLtot of 0.11 L/h/kg, and Vdss of 0.34 L/kg. Oral administration (3 mg/kg, in 0.5% methylcellulose) resulted in AUC of 191 μM·h, MRT of 5.6 hours, and F of 106% [2].
Dog PK: In dogs, intravenous administration (1 mg/kg, in DMSO) gave t₁/₂β of 5.5 hours, CLtot of 0.03 L/h/kg, and Vdss of 0.19 L/kg. Oral administration (3 mg/kg, in 0.5% methylcellulose) resulted in AUC of 1186 μM·h, MRT of 6.6 hours, and F of 64% [2].
Monkey PK: In cynomolgus monkeys, intravenous administration (1 mg/kg, in DMSO) gave t₁/₂β of 5.9 hours, CLtot of 0.19 L/h/kg, and Vdss of 0.36 L/kg. Oral administration (3 mg/kg, in 0.5% methylcellulose) resulted in AUC of 30.6 μM·h and MRT of 5.2 hours (F not calculated) [2].
Human Clinical PK: In a single-dose Phase I clinical trial in healthy volunteers (doses ranging from 30 to 1600 mg), plasma exposure of JTE-151 increased in a dose-dependent manner. For the 30 mg dose (n=6), Cmax was 1220 ± 896 ng/mL, tmax was 2.77 h (1.50-4.00), AUC_last was 6030 ± 1210 ng·h/mL, and t₁/₂ was 5.63 ± 1.85 h. For the 1600 mg dose (n=6), Cmax was 60700 ± 16200 ng/mL, tmax was 3.54 h (3.00-4.00), AUC_last was 371000 ± 156000 ng·h/mL, and t₁/₂ was 10.7 ± 5.94 h [2].

CYP Inhibition: JTE-151 showed weak direct inhibition against CYP2C8 (IC₅₀ = 6.8 μM). IC₅₀ values for other typical CYPs were >10 μM [2].
hERG Liability: JTE-151 showed a slight hERG liability with an IC₅₀ of 7.4 μM. No QTcF prolongation was observed in conscious dogs at doses up to 100 mg/kg BID [2].
Genotoxicity: The bacterial reverse mutation test (Ames test, 5 strains) and the chromosomal aberration test in cultured mammalian cells (CHL cells) were negative, indicating a low potential for genotoxicity [2].
GLP Toxicology Studies: One-month GLP-compliant toxicity studies in rats and dogs did not reveal any development-limiting toxicity [2].
Human Clinical Safety: In the Phase I clinical trial, no severe adverse events were observed up to the highest dose (1600 mg) [2].

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- Weak direct inhibition against CYP2C8 (IC₅₀ = 6.8 μM); IC₅₀ values for other typical CYPs >10 μM
- Slight hERG liability (IC₅₀ = 7.4 μM)
- No QTcF prolongation; low potential for genotoxicity
- One-month GLP-compliant toxicity studies in rats and dogs revealed no development-limiting toxicity

[1]. Practical Synthesis of Chiral 3-(Hydroxyiminomethyl)adipic Acid, a Key Intermediate of the ROR-γ Inhibitor JTE-151, via Crystallization-Induced Dynamic Resolution. Org. Process Res. Dev. 2023, 27, 2355−2364

[2]. Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development. J Med Chem . 2024 Jan 25;67(2):952-970.

JTE-151 is a novel, orally available RORγ inhibitor that was advanced to human clinical trials based on its high selectivity, good metabolic stability, and favorable safety profile [2].
The compound was identified through a structure-activity relationship (SAR) investigation prioritizing “drug-likeness” indices such as ligand efficiency (LE) and Fsp³ (fraction of sp³ carbons) to mitigate potential drawbacks associated with nuclear receptor ligands (e.g., poor selectivity, poor physicochemical properties) [2].
The cocrystal structure of JTE-151 bound to human RORγ (PDB 8X7E) revealed a U-shaped conformation in the ligand-binding pocket. The alkanoic acid pendant group projects outside the pocket, while the neopentyl cyclobutane motif makes favorable van der Waals contacts with hydrophobic side chains (Leu324, Phe388, Leu391, Ile397). Hydrogen bonding with Phe377 in the terminal amide region contributes to high affinity [2].
JTE-151 is intended for the treatment of Th17 cell-mediated autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis [2].

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JTE-151 is a small molecule ROR-γ inhibitor that has been brought to the clinical trial stage [1].
The compound consists of an isoxazole core with three unique substituents: a chirally substituted adipic acid monoamide part, a cyclopropyl group, and a cis-3-neopentylcyclobutyl group [1].
JTE-151 is intended for the treatment of autoimmune diseases including psoriasis, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel diseases [1].
The literature describes a practical synthesis of the chiral key intermediate for JTE-151 via crystallization-induced dynamic resolution, enabling the production of the API starting material candidate on a kilogram scale [1].

C28H37CLN2O4

501.06

500.244185

C, 62.46; H, 6.05; Cl, 7.09; N, 8.40; O, 16.00

1404380-58-0

1608139-41-8 (free acid); 1608139-42-9 (sodium)

71127425

Typically exists as Off-white to light yellow solid at room temperature

6.1

2

5

11

35

746

1

ClC1C=C(C)C=CC=1NC(C[C@H](CCC(=O)O)C1C(=C(C2CC(CC(C)(C)C)C2)ON=1)C1CC1)=O

YWTJAGLMNTUIMB-SYYJFZTOSA-N

InChI=1S/C28H37ClN2O4/c1-16-5-9-22(21(29)11-16)30-23(32)14-19(8-10-24(33)34)26-25(18-6-7-18)27(35-31-26)20-12-17(13-20)15-28(2,3)4/h5,9,11,17-20H,6-8,10,12-15H2,1-4H3,(H,30,32)(H,33,34)/t17?,19-,20?/m0/s1

(4S)-6-(2-chloro-4-methylanilino)-4-[4-cyclopropyl-5-[3-(2,2-dimethylpropyl)cyclobutyl]-1,2-oxazol-3-yl]-6-oxohexanoic acid

JTE-151; JTE151; JTE 151; 1404380-58-0; CHEMBL3314012; JVS2L11ROA;

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 (49.9 mM)

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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