| Identification | Back Directory | [Name]
11,15-Metheno-15H-pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6H)-one, 10-[4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl]-1-(difluoromethyl)-1,4,7,8,9,10-hexahydro-6-methyl-, (6R,10S)- | [CAS]
1802425-99-5 | [Synonyms]
BMS-986177
JNJ-70033093
Milvexian, BMS-986177 , JNJ-70033093
11,15-Metheno-15H-pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6H)-one, 10-[4-[5-chloro-2-(4-chloro-1
11,15-Metheno-15H-pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6H)-one, 10-[4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1(6H)-pyrimidinyl]-1-(difluoromethyl)-1,4,7,8,9,10-hexahydro-6-methyl-, (6R,10S)- | [Molecular Formula]
C28H23Cl2F2N9O2 | [MDL Number]
MFCD34469530 | [MOL File]
1802425-99-5.mol | [Molecular Weight]
626.45 |
| Chemical Properties | Back Directory | [density ]
1.60±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [form ]
Solid | [pka]
13.42±0.60(Predicted) | [color ]
White to off-white | [InChIKey]
FSWFYCYPTDLKON-FRHUOMFCNA-N | [SMILES]
C(N1N=CC2NC([C@@H](CCC[C@H](N3C=NC(C4C=C(Cl)C=CC=4N4N=NC(Cl)=C4)=CC3=O)C3N=CC=C(C=3)C1=2)C)=O)(F)F |&1:7,11,r| |
| Hazard Information | Back Directory | [Uses]
Milvexian is an orally bioavailable, small-molecule, reversible, direct antagonists of factor Xia, with the Ki of 0.11, 0.38, 0.64, 490, 350 nM for human, rabbit, dog, rat, mouse, respectively. Milvexian shows anti-thrombosis activity in vitro and in vivo, and can be used for thrombus study[1]. | [in vivo]
Milvexian (20 mg/kg for PO) produces average plasma concentrations of 2000 and 40 nM at 1 and 24 h after dosing, respectively[1].
Milvexian (0.8 mg/kg for i.v.) produces average plasma concentrations of 2000 and 100 nM at 10 min and 8 h after dosing, respectively[1].
Milvexian (0.063-4 + 0.04- 2.68 mg/kg for i.v. plus a continuous infusion) inhibites the formation of thrombosis in vivo[2].
Pharmacokinetic Analysis in Rabbits[1]
| Route | Dose (mg/kg) | Clearance (mL/min/kg) | Volume of Distribution (L/kgL) | Half-life (h) | Oral Bioavailability (%) | | i.v./p.o. | 0.8/20 | 6.7 | 1.4 | 2.5 | 14 |
| Animal Model: | The rabbit electrically mediated carotid arterial thrombosis model[1] | | Dosage: | 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)
| | Administration: | Intravenous injection (i.v.) plus a continuous infusion | | Result: | Decreased carotid blood flow(CBF) to 32-76% and reduced thrombus weight by 15-70%.
Decreased CBF to 40% of control initiated after 15 min.
Decreased CBF to 39-66% after Seventy-five minutes.
|
| Animal Model: | The rabbit cuticle bleeding time model[1] | | Dosage: | Prevention: 0.063 + 0.04, 0.25 + 0.17, and 1 + 0.67 (mg/kg + mg/kg/h)
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)
| | Administration: | Intravenous injection (i.v.) plus a continuous infusion | | Result: | Did not increase the carotid blood flow(BT) with combination of Aspirin (HY-14654). |
| Animal Model: | The rabbit arteriovenous shunt model[2] | | Dosage: | Prevention: 0.063 + 0.04, 0.25 + 0.17, and 1 + 0.67 (mg/kg + mg/kg/h)
Prevention: 0.063 + 0.04, 0.25 + 0.17, and 1 + 0.67 (mg/kg + mg/kg/h)
0.25?+?0.17, 1.0?+?0.67, and 4.0?+?2.68 ?mg/kg
| | Administration: | Intravenous injection (i.v.) plus a continuous infusion | | Result: | Reduced thrombus weight of thrombosis by 34.3?-66.9?%.
Increased the prolongation of APTT with 1.54-3.12-fold, but did not alter the PT and TT.
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| [storage]
Store at -20°C | [References]
[1] Pancras C. Wong, et al. 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] Xinkang Wang, et al. 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] Wong P, et al. 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). |
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