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Purity: ≥98%
Branebrutinib (formerly BMS-986195) is a highly selective and rapidly acting covalent/irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK) with IC50 of<1 nM and robust efficacy at low doses in preclinical models of RA (Rheumatoid Arthritis) and Lupus Nephritishighly. BMS-986195 functions by covalently altering a cysteine residue located in the active site of BTK. Its selectivity varies from 9 to 1010 fold within the Tec family, and it is more than 5000 times selective for BTK over all other kinases. BMS-986195 rapidly inactivated BTK in human whole blood (3.5×10-4 nM-1·min-1) and potently inhibited B cell proliferation, CD86 expression, and antigen-dependent interleukin-6 production (IC50 <1 nM) without affecting antigen-independent measures in the same cells. Comparable efficacy was assessed in relation to FcγR-dependent TNF-α synthesis in human cells. After just the second dose, mice receiving a dose as low as 0.5 mg/kg orally (PO) daily (QD) had a 98% peak BTK inactivation. BTK was dose-dependently inactivated to comparable levels in the spleen, lymph nodes, and whole blood. In murine models of RA, such as CIA and CAIA, BMS-986195 showed strong efficacy in preventing clinically apparent disease, histologic joint damage, and loss of bone mineral density. The highest level of effectiveness was noted in both models at doses ≤0.5 mg/kg PO QD, which resulted in ≥95% inactivation of BTK in vivo. In the NZB/W mouse model of lupus, the compound was also highly protective against nephritis at similar doses. A single or multiple doses of BMS-986195 were administered to cynomolgus monkeys in order to study the dynamics of BTK inactivation and resynthesis. With a single dosage of BMS-986195 at 0.5 mg/kg PO, 100% peak inactivation of BTK was attained.
| Targets |
BTK (IC50 = 0.1 nM); TEC (IC50 = 0.9 nM); BMX (IC50 = 1.5 nM); TXK (IC50 = 5 nM)
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| ln Vitro |
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| Enzyme Assay |
BMS-986195 has proven to be highly effective in mitigating clinically apparent disease, histologic joint damage, and loss of bone mineral density in mice in murine models of RA, such as CIA and CAIA. The highest level of effectiveness is seen in both mice and monkeys at doses ≤0.5 mg/kg PO QD, which results in ≥95% inactivation of BTK in vivo. In the NZB/W mouse model of lupus, BMS-986195 is also highly protective against nephritis at similar doses. Single or multiple doses of BMS-986195 are administered to cynomolgus monkeys in order to study the dynamics of BTK inactivation and resynthesis. With a single dose of BMS-986195 at 0.5 mg/kg PO, 100% peak inactivation of BTK is achieved[1].
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| Cell Assay |
BMS-986195 effectively deactivates BTK in human whole blood at a speed of 3.5×10-4nM-1•min-1. It also significantly suppresses antigen-dependent interleukin-6 production, CD86 expression, and B cell proliferation (IC50<1 nM) in B cells, while having no effect on antigen-independent measures in them. Comparable efficacy is assessed in relation to FcγR-dependent TNF-α synthesis in human cells.
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| Animal Protocol |
NZB/W lupus-prone mouse model
0.2, 0.5, and 1.5 mg/kg by oral gavage |
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| References |
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| Additional Infomation |
Branebrutinib is under investigation in clinical trial NCT02705989 (Safety, Tolerability and Relative Bioavailability Study of BMS-986195 in Healthy Subjects).
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| Molecular Formula |
C20H23FN4O2
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| Molecular Weight |
370.43
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| Exact Mass |
370.18
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| Elemental Analysis |
C, 64.85; H, 6.26; F, 5.13; N, 15.13; O, 8.64
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| CAS # |
1912445-55-6
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| Related CAS # |
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| PubChem CID |
121293929
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| Appearance |
White to off-white solid powder
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| LogP |
2.8
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
657
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1C=C(C(N)=O)C2=C(C(C)=C(C)N2)C=1N1CCC[C@@H](C1)NC(C#CC)=O
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| InChi Key |
VJPPLCNBDLZIFG-ZDUSSCGKSA-N
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| InChi Code |
InChI=1S/C20H23FN4O2/c1-4-6-16(26)24-13-7-5-8-25(10-13)19-15(21)9-14(20(22)27)18-17(19)11(2)12(3)23-18/h9,13,23H,5,7-8,10H2,1-3H3,(H2,22,27)(H,24,26)/t13-/m0/s1
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| Chemical Name |
4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.75 mg/mL (10.12 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 37.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3.75 mg/mL (10.12 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 37.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6996 mL | 13.4978 mL | 26.9957 mL | |
| 5 mM | 0.5399 mL | 2.6996 mL | 5.3991 mL | |
| 10 mM | 0.2700 mL | 1.3498 mL | 2.6996 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 |
| NCT03245515 | Completed | Drug: BMS-986195 | Rheumatoid Arthritis | Bristol-Myers Squibb | August 15, 2017 | Phase 1 |
| NCT02705989 | Completed | Drug: BMS-986195 Other: Placebo |
Rheumatoid Arthritis | Bristol-Myers Squibb | August 18, 2016 | Phase 1 |
| NCT03131973 | Completed | Drug: BMS-986195 Drug: Methotrexate |
Rheumatoid Arthritis | Bristol-Myers Squibb | May 13, 2017 | Phase 1 |
| NCT05014438 | Completed | Drug: BMS-986166 Drug: Branebrutinib |
Dermatitis, Atopic | Bristol-Myers Squibb | August 17, 2021 | Phase 2 |
| NCT05303220 | Completed | Drug: Branebrutinib Drug: Placebo |
Healthy Volunteers | Bristol-Myers Squibb | April 8, 2022 | Phase 1 |
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