Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4

被引：15

作者：

Priestley, E. Scott ^{[2
,5
]}

Banville, Jacques ^{[1
]}

Deon, Daniel ^{[1
]}

Dube, Laurence ^{[1
]}

Gagnon, Marc ^{[1
]}

Guy, Julia ^{[1
]}

Lapointe, Philippe ^{[1
]}

Lavallee, Jean-Francois ^{[1
]}

Martel, Alain ^{[1
]}

Plamondon, Serge ^{[1
]}

Remillard, Roger ^{[1
]}

Ruediger, Edward ^{[1
]}

Tremblay, Francois ^{[1
]}

Posy, Shana L. ^{[2
]}

Guarino, Victor R. ^{[2
]}

Richter, Jeremy M. ^{[2
]}

Li, Jianqing ^{[2
]}

Gupta, Anuradha ^{[3
]}

Vetrichelvan, Muthalagu ^{[3
]}

Balapragalathan, T. J. ^{[3
]}

Mathur, Arvind ^{[2
]}

Hua, Ji ^{[2
]}

Callejo, Mario ^{[1
]}

Guay, Jocelyne ^{[1
]}

Sum, Chi Shing ^{[2
]}

Cvijic, Mary Ellen ^{[2
]}

Watson, Carol ^{[2
]}

Wong, Pancras ^{[2
]}

Yang, Jing ^{[2
]}

Bouvier, Michel ^{[1
,4
]}

Gordon, David A. ^{[2
]}

Wexler, Ruth R. ^{[2
]}

Marinier, Anne ^{[1
,6
,7
]}

机构：

[1] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada

[2] Bristol Myers Squibb Res & Early Dev, Princeton, NJ 08540 USA

[3] Syngene Int Ltd, Dept Discovery Synth, Biocon Bristol Myers Squibb R&D Ctr, Bangalore 560099, Karnataka, India

[4] Univ Montreal, Dept Biochem & Mol Med, Montreal, PQ H3C 3J7, Canada

[5] Proteovant Therapeut, 2500 Renaissance Blvd, King Of Prussia, PA 19406 USA

[6] Univ Montreal, Dept Chem, Montreal, PQ H3C 3J7, Canada

[7] Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年

关键词：

CLOPIDOGREL; PREVENTION; THROMBOSIS; VORAPAXAR; INHIBITOR; POTENT;

D O I：

10.1021/acs.jmedchem.2c00359

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.

引用

页码：8843 / 8854

页数：12

共 4 条

[1] PAR4 (Protease-Activated Receptor 4) Antagonism With BMS-986120 Inhibits Human Ex Vivo Thrombus Formation
Wilson, Simon J.
Ismat, Fraz A.
Wang, Zhaoqing
Cerra, Michael
Narayan, Hafid
Raftis, Jennifer
Gray, Timothy J.
Connell, Shea
Garonzik, Samira
Ma, Xuewen
Yang, Jing
Newby, David E.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2018, 38 (02) : 448 - 456
[2] New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans
Merali, Samira
Wang, Zhaoqing
Frost, Charles
Callejo, Mario
Hedrick, Michael
Hui, Lester
Shropshire, Stephanie Meadows
Xu, Ke
Bouvier, Michel
DeSouza, Mary M.
Yang, Jing
PLATELETS, 2022, 33 (07) : 969 - 978
[3] An Orally-Active Small-Molecule Antagonist of the Platelet Protease-Activated Receptor-4, BMS-986141, Prevents Aeterial Thrombosis With Low Bleeding Liability in Cynomolgus Monkeys
Wong, Pancras C.
Watson, Carol A.
Bostwick, Jeffery
Banville, Jacques
Wexler, Ruth R.
Priestley, E. S.
Marinier, Anne
Bouvier, Michel
Gordon, David
Schumacher, William
Yang, Jing
CIRCULATION, 2017, 136
[4] Discovery of quinazoline-benzothiazole derivatives as novel potent protease-activated receptor 4 antagonists with improved pharmacokinetics and low bleeding liability
Li, Shanshan
Liu, Shangde
Yuan, Duo
Liu, Renjie
Hu, Lifang
Zhu, Xiong
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2024, 280

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