Milvexian, an orally bioavailable, small-molecule, reversible, direct inhibitor of factor XIa: In vitro studies and in vivo evaluation in experimental thrombosis in rabbits.

Animals Carotid Artery Thrombosis / drug therapy Factor XIa Fibrinolytic Agents / therapeutic use Partial Thromboplastin Time Rabbits Thrombosis / drug therapy
antithrombotic blood coagulation factor XIa inhibitor hemostasis thrombosis

Journal

Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508

Informations de publication

Date de publication:
02 2022
Historique:
revised: 12 10 2021
received: 23 08 2021
accepted: 05 11 2021
pubmed: 10 11 2021
medline: 16 3 2022
entrez: 9 11 2021
Statut: ppublish

Résumé

Milvexian (BMS-986177/JNJ-70033093) is an orally bioavailable factor XIa (FXIa) inhibitor currently in phase 2 clinical trials. To evaluate in vitro properties and in vivo characteristics of milvexian. In vitro properties of milvexian were evaluated with coagulation and enzyme assays, and in vivo profiles were characterized with rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT). Milvexian is an active-site, reversible inhibitor of human and rabbit FXIa (K Milvexian is an effective antithrombotic agent with limited impact on hemostasis, even when combined with aspirin in rabbits. This study supports inhibition of FXIa with milvexian as a promising antithrombotic therapy with a wide therapeutic window.

Sections du résumé

BACKGROUND
Milvexian (BMS-986177/JNJ-70033093) is an orally bioavailable factor XIa (FXIa) inhibitor currently in phase 2 clinical trials.
OBJECTIVES
To evaluate in vitro properties and in vivo characteristics of milvexian.
METHODS
In vitro properties of milvexian were evaluated with coagulation and enzyme assays, and in vivo profiles were characterized with rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT).
RESULTS
Milvexian is an active-site, reversible inhibitor of human and rabbit FXIa (K
CONCLUSIONS
Milvexian is an effective antithrombotic agent with limited impact on hemostasis, even when combined with aspirin in rabbits. This study supports inhibition of FXIa with milvexian as a promising antithrombotic therapy with a wide therapeutic window.

Identifiants

DOI: 10.1111/jth.15588 PMID: 34752670 PMC: PMC9299130
pubmed: 34752670
doi: 10.1111/jth.15588
pmc: PMC9299130
pii: S1538-7836(22)02807-0
doi:

Substances chimiques

Fibrinolytic Agents 0
Factor XIa EC 3.4.21.27

Types de publication

Clinical Trial, Phase II Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

399-408

Commentaires et corrections

Type : ErratumIn

Informations de copyright

© 2021 Bristol Myers Squibb. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

Références

Thromb Haemost. 2010 Aug;104(2):261-9
pubmed: 20589312
J Med Chem. 2022 Feb 10;65(3):1770-1785
pubmed: 34494428
Arterioscler Thromb Vasc Biol. 2016 Jul;36(7):1316-22
pubmed: 27174099
Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):388-92
pubmed: 20139363
N Engl J Med. 2015 Jan 15;372(3):232-40
pubmed: 25482425
Res Pract Thromb Haemost. 2021 May 28;5(4):e12524
pubmed: 34095733
J Thromb Thrombolysis. 2010 Jan;29(1):70-80
pubmed: 19851712
Blood. 2011 Jul 14;118(2):437-45
pubmed: 21527525
J Thromb Thrombolysis. 2011 Aug;32(2):129-37
pubmed: 21614454
J Thromb Thrombolysis. 2015 Nov;40(4):416-23
pubmed: 26249722
Blood. 2011 Nov 10;118(19):5302-11
pubmed: 21821705
Arterioscler Thromb Vasc Biol. 2018 Feb;38(2):304-310
pubmed: 29269514
Thromb Haemost. 2009 Jan;101(1):108-15
pubmed: 19132196
J Thromb Haemost. 2009 Jul;7 Suppl 1:84-7
pubmed: 19630775
Thromb Haemost. 2012 Jun;107(6):1141-50
pubmed: 22398951
J Thromb Haemost. 2007 Dec;5(12):2323-9
pubmed: 17883591
J Med Chem. 2018 Sep 13;61(17):7425-7447
pubmed: 29775297
J Thromb Haemost. 2008 May;6(5):820-9
pubmed: 18315548
Mol Ther Nucleic Acids. 2015 Jan 27;4:e224
pubmed: 25625614
J Pharmacol Exp Ther. 2000 Oct;295(1):212-8
pubmed: 10991981
Clin Transl Sci. 2022 Feb;15(2):330-342
pubmed: 34558200
J Thromb Haemost. 2022 Feb;20(2):399-408
pubmed: 34752670
J Cardiovasc Pharmacol. 2007 May;49(5):316-24
pubmed: 17513951
Br J Haematol. 2017 Nov;179(3):506-508
pubmed: 27392111
JAMA. 2020 Jan 14;323(2):130-139
pubmed: 31935028
Blood. 2010 Apr 1;115(13):2569-77
pubmed: 20110423

Auteurs

Pancras C Wong (PC)

Cardiovascular and Fibrosis Drug Discovery Biology, Bristol Myers Squibb Company, Princeton, New Jersey, USA.
ORCID: 0000-0002-8224-7423

Earl J Crain (EJ)

Cardiovascular and Fibrosis Drug Discovery Biology, Bristol Myers Squibb Company, Princeton, New Jersey, USA.

Jeffrey M Bozarth (JM)

Cardiovascular and Fibrosis Drug Discovery Biology, Bristol Myers Squibb Company, Princeton, New Jersey, USA.

Yiming Wu (Y)

Cardiovascular and Fibrosis Drug Discovery Biology, Bristol Myers Squibb Company, Princeton, New Jersey, USA.

Andrew K Dilger (AK)

Cardiovascular Drug Discovery Chemistry, Bristol Myers Squibb Company, Princeton, New Jersey, USA.

Ruth R Wexler (RR)

Cardiovascular Drug Discovery Chemistry, Bristol Myers Squibb Company, Princeton, New Jersey, USA.

William R Ewing (WR)

Cardiovascular Drug Discovery Chemistry, Bristol Myers Squibb Company, Princeton, New Jersey, USA.

David Gordon (D)

Cardiovascular and Fibrosis Drug Discovery Biology, Bristol Myers Squibb Company, Princeton, New Jersey, USA.

Joseph M Luettgen (JM)

Cardiovascular and Fibrosis Drug Discovery Biology, Bristol Myers Squibb Company, Princeton, New Jersey, USA.
ORCID: 0000-0002-5067-8819

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Milvexian, an orally bioavailable,...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Embolie et thrombose › Thromboembolie › Embolie et thrombose intracrâniennes › Thrombose carotidienne › Milvexian, an orally bioavailable,...
questionsmedicales.fr › Facteurs biologiques › Facteurs de la coagulation sanguine › Facteur XI › Facteur XIa › Milvexian, an orally bioavailable,...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents hématologiques › Fibrinolytiques › Milvexian, an orally bioavailable,...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiogiques du sang › Temps partiel de thromboplastine › Milvexian, an orally bioavailable,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Lagomorpha › Lapins › Milvexian, an orally bioavailable,...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Embolie et thrombose › Thrombose › Milvexian, an orally bioavailable,...