-transparent.png){kind=logo}
Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis. 2024
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
Research & Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low μM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.
| UI | MeSH Term | Description | Entries |
|---|
Related Publications
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
April 2024,
ACS pharmacology & translational science,
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
December 2021,
European journal of medicinal chemistry,
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
August 2019,
Journal of medicinal chemistry,
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
October 2014,
Bioorganic & medicinal chemistry letters,
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
August 2017,
Journal of medicinal chemistry,
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
February 2018,
Arteriosclerosis, thrombosis, and vascular biology,
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
April 2024,
Journal of medicinal chemistry,
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
February 2018,
International journal of molecular sciences,
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
January 2021,
European journal of medicinal chemistry,
Xiaojun Zhang, and
Wen Jiang, and
Jeremy M Richter, and
J Alex Bates, and
Samuel K Reznik, and
Sylwia Stachura, and
Richard Rampulla, and
Dyamanna Doddalingappa, and
Sankar Ulaganathan, and
Ji Hua, and
Jeffrey S Bostwick, and
Chi Sum, and
Shana Posy, and
Sarah Malmstrom, and
Joyce Dickey, and
David Harden, and
R Michael Lawrence, and
Victor R Guarino, and
William A Schumacher, and
Pancras Wong, and
Jing Yang, and
David A Gordon, and
Ruth R Wexler, and
E Scott Priestley
March 2003,
Current medicinal chemistry. Cardiovascular and hematological agents,
