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Milvexian (BMS986177; JNJ70033093) is a coagulation factor XIa inhibitor that is orally-bioavailable. It acts as a reversible and direct inhibitor of human and rabbit factor XIa (FXIa) with Ki of 0.11, and 0.38 nM, respectively.
Physicochemical Properties
| Molecular Formula | C28H23CL2F2N9O2 |
| Molecular Weight | 626.4441 |
| Exact Mass | 625.131 |
| CAS # | 1802425-99-5 |
| Related CAS # | 1802426-00-1 (TFA);1802425-99-5; |
| PubChem CID | 118277544 |
| Appearance | White to off-white solid powder |
| Density | 1.60±0.1 g/cm3 |
| LogP | 4 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 43 |
| Complexity | 1100 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | C[C@@H]1CCC[C@@H](C2=NC=CC(=C2)C3=C(C=NN3C(F)F)NC1=O)N4C=NC(=CC4=O)C5=C(C=CC(=C5)Cl)N6C=C(N=N6)Cl |
| InChi Key | FSWFYCYPTDLKON-CMJOXMDJSA-N |
| InChi Code | InChI=1S/C28H23Cl2F2N9O2/c1-15-3-2-4-23(20-9-16(7-8-33-20)26-21(36-27(15)43)12-35-41(26)28(31)32)39-14-34-19(11-25(39)42)18-10-17(29)5-6-22(18)40-13-24(30)37-38-40/h5-15,23,28H,2-4H2,1H3,(H,36,43)/t15-,23+/m1/s1 |
| Chemical Name | (9R,13S)-13-[4-[5-chloro-2-(4-chlorotriazol-1-yl)phenyl]-6-oxopyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetrazatricyclo[12.3.1.02,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one |
| 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) |
Biological Activity
| ln Vitro | Milvexian (about 10 μM) has no effect on collagen in ADP, arachidonic acid, or human activation, although it can lengthen the activation period of partial powder activation [1]. |
| ln Vivo | At one and two days following modeling, the mean venous concentrations of mildvexian (20 mg/kg, intravenous) were 2000 and 40 nM, respectively [1]. Milvexian (intravenous infusion, 0.8 mg/kg) For an average of roughly 10 minutes and 8 hours, mildvexian (0.063-4 + 0.04-2.68 mg/kg, intravenous infusion plus continuous intravenous infusion) can suppress thrombosis [2]. Rabbit pharmacokinetics. Examination [1] The dosage by route (mg/kg) Resolved (mL/min/kg) Distribution volume (L/kgL) Half-life (h) % of oral bioavailability iv/po 18 6.7 1.4 2.5 14 |
| Animal Protocol |
Animal/Disease Models: Rabbit electrically mediated carotid thrombosis model [1] Doses: Prevention: 0.063 + 0.04, 0.25 + 0.17 and 1 + 0.67 (mg/kg + mg/kg/h) Treatment: 0.25 + 0.17 and 1 + 0.67 ( mg /kg + mg/kg/h) Route of Administration: intravenous (iv) (iv)injection plus continuous infusion. Experimental Results: Carotid blood flow (CBF) was diminished to 32-76%, and thrombus weight was diminished by 15-70%. CBF diminished to 40% of control value after 15 minutes. After seventy-five minutes CBF diminished to 39-66%. Animal/Disease Models: Rabbit cuticle bleeding time model [1] Doses: Prevention: 0.063+0.04, 0.25+0.17, 1+0.67 (mg/kg+mg/kg/h) Prevention: 0.063+0.04, 0.25+0.17, 1 + 0.67 (mg/kg + mg/kg/h) Treatment: 0.25 + 0.17 and 1 + 0.67 (mg/kg + mg/kg/h) Route of Administration: intravenous (iv) (iv)(iv) plus continuous infusion Experimental Results: Not coadministered with aspirin Can increase carotid blood flow (BT). Animal/Disease Models: Rabbit arteriovenous shunt model [2] Doses: Prevention: 0.063 + 0.04, 0.25 + 0.17, 1 + 0.67 (mg/kg + mg/kg/h) Prevention: 0.063 + 0.04, 0.25 + 0.17, 1 + 0.67 (mg/kg + mg/kg/h) 0.25 + 0.17, 1.0 + 0.67 and 4.0 + 2.68 mg/kg Route of Administration: intravenous (iv) (iv)injection plus continuous infusion Experimental Results: thrombus weight diminished by 34.3 -66.9%. APTT prolongation time increased 1.54-3.12 times, but did not change PT and TT. |
| References |
[1]. Milvexian, an orally bioavailable, small‐molecule, reversible, direct inhibitor of factor XIa: In vitro studies and in vivo evaluation in experimental thrombosis in rabbits. [2]. Antithrombotic Effects of the Novel Small-Molecule Factor XIa Inhibitor Milvexian in a Rabbit Arteriovenous Shunt Model of Venous Thrombosis. TH Open. 2023 Apr; 7(2): e97–e104. [3]. Small-Molecule Factor XIa Inhibitor, BMS-986177/JNJ-70033093, Prevents and Treats Arterial Thrombosis in Rabbits at Doses that Preserve Hemostasis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). |
| Additional Infomation | Milvexian is under investigation in clinical trial NCT03766581 (A Study on BMS-986177 for the Prevention of a Stroke in Patients Receiving Aspirin and Clopidogrel). |
Solubility Data
| Solubility (In Vitro) | DMSO : ≥ 100 mg/mL (~159.63 mM) |
| 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 (e.g. IP/IV/IM/SC) 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). 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) 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). 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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5963 mL | 7.9816 mL | 15.9632 mL | |
| 5 mM | 0.3193 mL | 1.5963 mL | 3.1926 mL | |
| 10 mM | 0.1596 mL | 0.7982 mL | 1.5963 mL |