| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
Retinoic acid receptor-related orphan receptor γt (RORγt) [1].
EC₅₀: 12 ± 6 nM (in RORγt GAL4 reporter assay) [1]. EC₅₀: 24 ± 6 nM (in IL-17 human whole blood assay) [1]. EC₅₀: 11 ± 2 nM (in mouse Th17 assay) [1]. RORγt 12 nM (EC50); IL-17 24 nM (EC50); RORα >10 μM (EC50) RORβ >10 μM (EC50) |
|---|---|
| ln Vitro |
BMS-986251 is antagonistic against additional nuclear receptors (PXR: EC50>5 μM; LXRα: EC50>7.5 μM; LXRβ: EC50>7.5 μM) as well as members of the ROR family (RORα GAL4: EC50>10 μM; RORβ GAL4: EC50>10 μM). None of the CYPs are inhibited by BMS-986251[1].
In a RORγt GAL4 reporter assay (Jurkat cell line), BMS-986251 exhibited potent inverse agonist activity with an EC₅₀ of 12 ± 6 nM [1]. In an IL-17 human whole blood assay, BMS-986251 inhibited IL-17 production with an EC₅₀ of 24 ± 6 nM [1]. In a mouse Th17 reporter assay, BMS-986251 showed an EC₅₀ of 11 ± 2 nM, correlating well with human values [1]. BMS-986251 demonstrated high selectivity for RORγt over other ROR family members, with EC₅₀ values >10,000 nM for both RORα and RORβ in GAL4 reporter assays [1]. It also showed selectivity against other nuclear receptors, with EC₅₀ values >5000 nM for PXR, >7500 nM for LXRα, and >7500 nM for LXRβ [1]. In Caco-2 permeability assays, BMS-986251 demonstrated good permeability with an A-B transport rate of 240 nm/s and an efflux ratio of 0.5, indicating low active efflux [1]. BMS-986251 did not inhibit the tested cytochrome P450 enzymes, with IC₅₀ values >20 μM for CYP 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 (BFC substrate) [1]. The compound exhibited excellent stability in liver microsomes from human, mouse, and rat, with half-life >120 minutes across all three species [1]. |
| ln Vivo |
Ear thickness is decreased by BMS-986251 (5–45 mg/kg; oral; twice daily until day 9)[1]. Orally administered once daily, BMS-986251 (0.13, 0.79, 4.76 mg/kg) exhibits a dose-dependent decrease in the amount of IL-17F generated in naïve C57BL/6 female mice (7-9 weeks)[1]. For IV usage in mice, BMS-986251 (2 mg/kg and 4 mg/kg) has a T1/2 of 7.7 hours, a CL of 2.7 mL/min·kg, and a Vss of 1.9 L/kg[1].
IL-2/IL-23 Stimulated Mouse Pharmacodynamic Model: In female C57BL/6 mice, oral administration of BMS-986251 (0.13, 0.79, and 4.76 mg/kg, once daily) resulted in a dose-dependent reduction of IL-17F production in serum. The vehicle was 5% NMP, 76% PEG400, and 19% TPGS [1]. Mouse Acanthosis Model (Psoriasis Model): In C57BL/6 female mice, IL-23 was injected into the right ear every other day for 9 days to induce acanthosis. Oral administration of BMS-986251 (twice daily) significantly reduced ear thickness compared to the vehicle control, demonstrating robust efficacy comparable to a human anti-IL-23 positive control [1]. Imiquimod (IMQ)-Induced Mouse Model: BMS-986251 was evaluated in the IMQ-induced mouse model of skin inflammation, where it demonstrated robust efficacy (data shown in Figure 5) [1]. |
| Enzyme Assay |
RORγt GAL4 Reporter Assay: This assay was used to evaluate the inverse agonist activity of compounds against RORγt in a Jurkat cell line. Cells were transfected with a construct containing the GAL4 DNA-binding domain fused to the RORγt ligand-binding domain and a luciferase reporter gene. After 24 hours, compounds were added, and luciferase activity was measured after an additional 18-hour incubation to determine EC₅₀ values [1].
|
| Cell Assay |
IL-17 Human Whole Blood Assay: Human whole blood was collected and stimulated with appropriate activators to induce IL-17 production. Compounds were added at various concentrations, and after incubation, IL-17 levels were measured to determine the EC₅₀ for inhibition [1].
Mouse Th17 Assay: A mouse reporter assay was used to evaluate the activity of BMS-986251 against mouse RORγt. The EC₅₀ was determined to be 11 ± 2 nM, showing good correlation with human activity [1]. Caco-2 Permeability Assay: Caco-2 cell monolayers were used to assess the permeability of BMS-986251. The compound was added to the apical side, and transport to the basolateral side was measured. The efflux ratio was calculated as the ratio of basolateral-to-apical transport over apical-to-basolateral transport [1]. |
| Animal Protocol |
Animal/Disease Models: C57BL/6 female mice with acanthosis[1]
Doses: 5, 15, 45 mg /kg Route of Administration: po (oral gavage) twice (two times) daily until day 9 Experimental Results: Resulted in decreased ear thickness and Dramatically reduces imiquimod (IMQ)-induced skin thickening. Animal/Disease Models: Mouse or rat[1] Doses: 2 mg/kg of IV and 4 mg /kg of PO (pharmacokinetic/PK Analysis) Route of Administration: IV or PO Experimental Results: Had a T1/2 of 7.7 hrs (hours), a CL of 2.7 mL/min·kg, and a Vss of 1.9 L/kg for IV in mouse. Had a Cmax of 4.8 μM and an AUC of 37 μM·h for PO in mouse. Had a T1/2 of 11 hrs (hours), a CL of 1.3 mL/min·kg, and a Vss of 1.25 L/kg for IV in rat. Had a Cmax of 4.7 μM and an AUC of 64 μM·h for PO in rat. IL-2/IL-23 Stimulated Mouse PD Model: Female C57BL/6 mice (7-9 weeks old) were used. IL-2 (5 μg/mouse) was injected intraperitoneally at -24, 0, and 23 hours; IL-2 (10 μg/mouse) was also injected at 7 hours. IL-23 (1 μg/mouse) was injected intraperitoneally at 0, 7, and 23 hours. BMS-986251 was dosed orally once daily at 0.13, 0.79, and 4.76 mg/kg, 30 minutes prior to the 0-hour time point. The vehicle was 5% NMP, 76% PEG400, and 19% TPGS. Blood was collected at the 30-hour time point for exposure and serum IL-17F analysis [1]. Mouse Acanthosis Model: Female C57BL/6 mice were injected with recombinant humanized IL-23 into the right ear every other day for 9 days. Ear thickness was measured on day 0 (baseline) and then every other day prior to the next injection. BMS-986251 was dosed orally approximately 2 hours before the first IL-23 injection and continued twice daily until day 9. The placebo group received vehicle, and a human anti-IL-23 antibody was administered subcutaneously as a positive control [1]. Mouse PK Studies: For oral pharmacokinetic studies, Balb/c mice were dosed at 10 mg/kg PO. The vehicle was 5% NMP, 76% PEG400, and 19% TPGS. Values are means from three mice [1]. Preclinical PK Studies: For pharmacokinetic studies across species, BMS-986251 was administered intravenously and orally to mice (2 mg/kg iv, 4 mg/kg po), rats (2 mg/kg iv, 4 mg/kg po), dogs (1 mg/kg iv, 1 mg/kg po), and cynomolgus monkeys (1 mg/kg iv, 1 mg/kg po). Values are means from three or more animals [1]. |
| ADME/Pharmacokinetics |
Mouse PK: In Balb/c mice dosed orally at 10 mg/kg, BMS-986251 showed Cmax of 11 ± 8 μM, AUC₂₄ₕ of 68 ± 50 μM·h, and C₂₄ₕ of 0.52 ± 0.13 μM [1].
Cross-Species PK: BMS-986251 demonstrated excellent oral bioavailability across species: ~100% in mouse (2 mg/kg iv, 4 mg/kg po), 94% in rat (2 mg/kg iv, 4 mg/kg po), ~100% in dog (1 mg/kg iv, 1 mg/kg po), and ~100% in cynomolgus monkey (1 mg/kg iv, 1 mg/kg po) [1]. Clearance: The compound exhibited low clearance in all species tested: mouse (2.7 mL/min/kg), rat (1.3 ± 0.3 mL/min/kg), dog (0.18 ± 0.04 mL/min/kg), and cynomolgus monkey (1.1 ± 0.2 mL/min/kg) [1]. Half-Life: The terminal half-life was 7.7 hours in mouse, 11 ± 0.8 hours in rat, 36 ± 3 hours in dog, and 33 ± 4 hours in cynomolgus monkey [1]. Volume of Distribution: Vss values were 1.9 L/kg in mouse, 1.2 ± 0.3 L/kg in rat, 0.5 ± 0.1 L/kg in dog, and 2.0 ± 0.4 L/kg in cynomolgus monkey [1]. Liver Microsome Stability: BMS-986251 showed excellent stability in liver microsomes with half-life >120 minutes for human, mouse, and rat [1]. |
| Toxicity/Toxicokinetics |
CYP Inhibition: BMS-986251 did not inhibit recombinant cytochrome P450 enzymes, with IC₅₀ values >20 μM for CYP 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 (BFC substrate) [1].
Protein Binding: The free fraction (unbound) of BMS-986251 was 1.2% in human plasma, 1.6% in mouse plasma, and 2.1% in rat plasma [1]. Nuclear Receptor Selectivity: BMS-986251 showed no significant activity against PXR (EC₅₀ >5000 nM), LXRα (EC₅₀ >7500 nM), or LXRβ (EC₅₀ >7500 nM), indicating low risk for off-target effects [1]. Additional Info: BMS-986251 is a novel tricyclic RORγt inverse agonist that was selected as a clinically viable developmental candidate based on its excellent overall profile [1]. The compound was designed based on X-ray crystal structure analysis of a previous lead compound (compound 2) in RORγt, which revealed that the cyclohexane ring came in close proximity to helix 5 of the receptor. Optimization focused on introducing substituents to improve affinity [1]. The crystal structure of BMS-986251 bound to RORγt (pdb id: 6VQF) shows its binding mode, with key interactions including the carboxylate interacting with Arg367 and Arg364, and the amide carbonyl engaging the backbone NH of Phe377 [1]. BMS-986251 is intended for the treatment of autoimmune diseases such as psoriasis, where Th17 cells and IL-17 play a critical pathogenic role [1]. |
| References | |
| Additional Infomation |
BMS-986251 is a novel tricyclic RORγt inverse agonist that was selected as a clinically viable developmental candidate based on its excellent overall profile [1].
The compound was designed based on X-ray crystal structure analysis of a previous lead compound (compound 2) in RORγt, which revealed that the cyclohexane ring came in close proximity to helix 5 of the receptor. Optimization focused on introducing substituents to improve affinity [1]. The crystal structure of BMS-986251 bound to RORγt (pdb id: 6VQF) shows its binding mode, with key interactions including the carboxylate interacting with Arg367 and Arg364, and the amide carbonyl engaging the backbone NH of Phe377 [1]. BMS-986251 is intended for the treatment of autoimmune diseases such as psoriasis, where Th17 cells and IL-17 play a critical pathogenic role [1]. |
| Molecular Formula |
C30H29F8NO5S
|
|---|---|
| Molecular Weight |
667.61
|
| Exact Mass |
667.163
|
| Elemental Analysis |
C, 53.97; H, 4.38; F, 22.77; N, 2.10; O, 11.98; S, 4.80
|
| CAS # |
2460133-35-9
|
| Related CAS # |
2460133-35-9;2041841-30-7
|
| PubChem CID |
132123624
|
| Appearance |
Typically exists as solid at room temperature
|
| LogP |
6.1
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
13
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
45
|
| Complexity |
1230
|
| Defined Atom Stereocenter Count |
5
|
| SMILES |
C[C@H]1C[C@@H](CC[C@H]1C(=O)N2CC[C@@]3([C@H]2CCC4=C3C=CC(=C4)C(C(F)(F)F)(C(F)(F)F)F)S(=O)(=O)C5=CC=C(C=C5)F)C(=O)O
|
| InChi Key |
JQORWGARJVSRBA-QOTTZFGFSA-N
|
| InChi Code |
InChI=1S/C30H29F8NO5S/c1-16-14-18(26(41)42)2-9-22(16)25(40)39-13-12-27(45(43,44)21-7-5-20(31)6-8-21)23-10-4-19(15-17(23)3-11-24(27)39)28(32,29(33,34)35)30(36,37)38/h4-8,10,15-16,18,22,24H,2-3,9,11-14H2,1H3,(H,41,42)/t16-,18+,22+,24+,27+/m0/s1
|
| Chemical Name |
(1R,3S,4R)-4-[(3aR,9bR)-9b-(4-fluorophenyl)sulfonyl-7-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,3a,4,5-tetrahydro-1H-benzo[e]indole-3-carbonyl]-3-methylcyclohexane-1-carboxylic acid
|
| Synonyms |
BMS-986251; BMS 986251; UNII-2WQX2MS3MQ; BMS986251; 2WQX2MS3MQ; (1R,3S,4R)-4-((3aR,9bR)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo(E)indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid; 2041841-30-7;
|
| 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
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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 | 1.4979 mL | 7.4894 mL | 14.9788 mL | |
| 5 mM | 0.2996 mL | 1.4979 mL | 2.9958 mL | |
| 10 mM | 0.1498 mL | 0.7489 mL | 1.4979 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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