BMS-986165

Product NameBMS-986165
CAS1802425-99-5
MFC28H23Cl2F2N9O2
MW626.45
EINECS
MOL File1802425-99-5.mol

Chemical Properties

Density	1.60±0.1 g/cm3(Predicted)
storage temp.	Store at -20°C
pka	13.42±0.60(Predicted)
form	Solid
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\|

Usage And Synthesis

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.

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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