Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy

被引：12

作者：

Miller, Michael M. ^{[1
,3
]}

Banville, Jacques ^{[2
]}

Friends, Todd J. ^{[1
,6
]}

Gagnon, Mark ^{[2
]}

Hangeland, Jon J. ^{[1
,6
]}

Lavallee, Jean-Francois ^{[2
]}

Martel, Alain ^{[2
]}

O'Grady, Harold ^{[1
]}

Remillard, Roger ^{[2
]}

Ruediger, Edward ^{[2
]}

Tremblay, Francois ^{[2
]}

Posy, Shana L. ^{[1
]}

Allegretto, Nick J. ^{[1
]}

Guarino, Victor R. ^{[1
]}

Harden, David G. ^{[1
,4
]}

Harper, Timothy W. ^{[1
]}

Hartl, Karen ^{[1
]}

Josephs, Jonathan ^{[1
]}

Malmstrom, Sarah ^{[1
]}

Watson, Carol ^{[1
]}

Yang, Yanou ^{[1
]}

Mang, Ge ^{[1
]}

Wong, Pancras ^{[1
]}

Yang, Wongjing ^{[1
]}

Bouvier, Michel ^{[2
,5
]}

Seiffert, Dietmar A. ^{[1
,3
]}

Wexler, Ruth R. ^{[1
,6
]}

Lawrence, R. Michael ^{[1
,6
]}

Priestley, E. Scott ^{[1
,6
]}

Marinier, Anne ^{[2
]}

机构：

[1] Bristol Myers Squibb Res & Dev, 311 Pennington Rocky Hill Rd, Pennington, NJ 08534 USA

[2] Univ Montreal, Inst Res Immunol & Canc, Downtown Stn, POB 6128, Montreal, PQ H3C 3J7, Canada

[3] Bristol Myers Squibb Res & Dev, 3551 Lawrenceville Rd, Princeton, NJ 08540 USA

[4] Bristol Myers Squibb Res & Dev, 5 Res Pkwy, Wallingford, CT 06492 USA

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

[6] Bristol Myers Squibb Res & Dev, 350 Carter Rd, Hopewell, NJ 08540 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 16期

关键词：

ACUTE CORONARY SYNDROMES; THROMBIN-RECEPTOR; PLATELET ACTIVATION; PAR4; ANTAGONISTS; THERAPY; CLOPIDOGREL; INHIBITION; PREVENTION; VORAPAXAR; PRASUGREL;

D O I：

10.1021/acs.jmedchem.9b00186

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

引用

页码：7400 / 7416

页数：17

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