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Purity: ≥98%
Evobrutinib is discontinued due to commercial reason. Evobrutinib (formerly known as M2951 and MSC-2364447C) is a novel, orally bioactive, potent, highly selective and irreversible/covalent BTK ( Bruton’s tyrosine kinase) inhibitor with IC50 of 8.9 nM.It may be used to treat autoimmune conditions. BTK is essential for the growth and operation of many immune cells, such as macrophages and B lymphocytes. According to preclinical research, it might be helpful as a treatment for some autoimmune illnesses. In vivo assessment in efficacy models was made possible by evobrutinib's satisfactory preclinical pharmacokinetic and pharmacodynamic features. Further evidence of a low risk of off-target related side effects came from evobrutinib's high selectivity for BTK over the Tec family kinases and the epidermal growth factor receptor. The autoimmune diseases multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus are among those for which evobrutinib is currently being studied in clinical settings. In the treatment of B cell malignancies, BTK inhibitors, like ibrutinib, are important. To evaluate this class of agents for non-oncology indications is impossible due to adverse events (which may be caused by kinase promiscuity). Therefore, more work needs to be done in terms of improvement.
| Targets |
BTK (IC50 = 37.9 nM)
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|---|---|
| ln Vitro |
Evobrutinib has the ability to block BTK activity and stop the BCR signaling pathway from being activated. It is broken down by GSH conjugation, O-dealkylation, hydroxylation, hydrolysis, and glucuronidation[2].
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| ln Vivo |
Evobrutinib is a novel, highly selective, irreversible BTK inhibitor that effectively blocks signaling mediated by Fc and BCR receptors.
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| Animal Protocol |
DBA/1J female mice
12 mg/kg o.g. |
| References |
| Molecular Formula |
C25H27N5O2
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|---|---|
| Molecular Weight |
429.5142
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| Exact Mass |
429.22
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| Elemental Analysis |
C, 69.91; H, 6.34; N, 16.31; O, 7.45
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| CAS # |
1415823-73-2
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| Related CAS # |
1415823-73-2
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| Appearance |
Solid powder
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| SMILES |
C=CC(=O)N1CCC(CC1)CNC2=NC=NC(=C2C3=CC=C(C=C3)OC4=CC=CC=C4)N
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| InChi Key |
QUIWHXQETADMGN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H27N5O2/c1-2-22(31)30-14-12-18(13-15-30)16-27-25-23(24(26)28-17-29-25)19-8-10-21(11-9-19)32-20-6-4-3-5-7-20/h2-11,17-18H,1,12-16H2,(H3,26,27,28,29)
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| Chemical Name |
1-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidin-1-yl]prop-2-en-1-one
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| Synonyms |
MSC-2364447-C; MSC-2364447 C; M-2951; M 2951; M2951; MSC-2364447C; MSC 2364447C; MSC2364447C
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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) |
DMSO: ~86 mg/mL (~200.2 mM)
Ethanol: ~10 mg/mL (~23.3 mM) |
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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 | 2.3282 mL | 11.6412 mL | 23.2823 mL | |
| 5 mM | 0.4656 mL | 2.3282 mL | 4.6565 mL | |
| 10 mM | 0.2328 mL | 1.1641 mL | 2.3282 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 |
| NCT04338061 | Active Recruiting |
Drug: Evobrutinib Drug: Teriflunomide |
Relapsing Multiple Sclerosis | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany |
July 2, 2020 | Phase 3 |
| NCT04338022 | Active Recruiting |
Drug: Evobrutinib Drug: Teriflunomide |
Relapsing Multiple Sclerosis | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany |
June 12, 2020 | Phase 3 |
| NCT02975349 | Active Recruiting |
Drug: Evobrutinib Drug: Placebo |
Relapsing-remitting Multiple Sclerosis |
EMD Serono Research & Development Institute, Inc. |
March 7, 2017 | Phase 2 |
| NCT03934502 | Completed | Drug: Evobrutinib | Healthy | Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany |
April 15, 2019 | Phase 1 |
| NCT03436394 | Completed | Drug: Evobrutinib | Renal Impairment C | Merck KGaA, Darmstadt, Germany | March 21, 2018 | Phase 1 |
Figure 1. X-ray structure of BTK ligandB43bound to the BTK kinase domain.J Med Chem.2019 Aug 15. doi: 10.1021/acs.jmedchem.9b00794. |
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 Figure 2. Overlay of crystal structures ofA5andA7.
Figure 5. Crystal structure of evobrutinib bound to the BTK kinase domain.J Med Chem.2019 Aug 15. doi: 10.1021/acs.jmedchem.9b00794. |
 Figure 3. PK/PD studies in mice.
Figure 6. Rat CIA model: rats treated with evobrutinib, MTX, or vehicle.J Med Chem.2019 Aug 15. doi: 10.1021/acs.jmedchem.9b00794. |
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