Author: Watson, Carol ; Plamondon, Serge ; Sum, Chi Shing ; Bouvier, Michel ; Martel, Alain ; Priestley, E. Scott ; Guy, Julia ; Wexler, Ruth R. ; Ruediger, Edward ; Li, Jianqing ; Gagnon, Marc ; Lavallée, Jean-François ; Gordon, David A. ; Yang, Jing ; Guarino, Victor R. ; Deon, Daniel ; Lapointe, Philippe ; Callejo, Mario ; Dubé, Laurence ; Vetrichelvan, Muthalagu ; Posy, Shana L. ; Guay, Jocelyne ; Cvijic, Mary Ellen ; Marinier, Anne ; Balapragalathan, T. J. ; Richter, Jeremy M. ; Mathur, Arvind ; Gupta, Anuradha ; Rémillard, Roger ; Hua, Ji ; Wong, Pancras ; Banville, Jacques ; Tremblay, François

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.

22 Aug 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Ruediger, Edward ; Hartl, Karen ; Malmstrom, Sarah ; Miller, Michael M. ; Wong, Pancras ; Rémillard, Roger ; Lavallée, Jean-François ; Yang, Yanou ; Allegretto, Nick J. ; Hangeland, Jon J. ; Priestley, E. Scott ; Yang, Jing ; Martel, Alain ; Bouvier, Michel ; Watson, Carol ; Harden, David G. ; Marinier, Anne ; Wexler, Ruth R. ; Harper, Timothy W. ; Posy, Shana L. ; Zhang, Ge ; O’Grady, Harold ; Friends, Todd J. ; Gagnon, Mark ; Seiffert, Dietmar A. ; Lawrence, R. Michael ; Josephs, Jonathan ; Tremblay, François ; Banville, Jacques ; Guarino, Victor R.

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.

01 Mar 2019·Journal of Theoretical and Computational Chemistry

Characterizing the interaction modes of PAR4 receptor with agonist and antagonist by molecular simulation approach

Author: Xu, Youjun ; Lu, Nan ; Yuan, Jing ; Zhao, Tong ; Xu, Weiren ; Meng, Fancui ; Li, Lingjun ; Tang, Lida ; Wang, Yanshi ; Liu, Lei

Protease-activated receptor 4 (PAR4) is a promising target for antiplatelet therapy. In this study, homology modeling and molecular docking methods were used to investigate the binding modes of PAR4 agonists and antagonists. The outcomes show that agonists have good docking scores, and they also form more hydrogen bonds with PAR4 than antagonists. To reveal the different conformational changes caused by agonist and antagonist, molecular dynamic simulations were carried out on three selected PAR4 systems. Simulation results show that PAR4 activation involves breaking interactions of 3–7 lock switch (Try157 and Tyr322) and ionic lock switch (Arg188 and Asp173), and formation of transmission switch among Tyr161, Asn300 and Phe296. In addition, principal component analysis (PCA) indicates that the major change for agonist bound system takes place in the intracellular region while that for antagonist bound system is in the extracellular region. The binding free energy of BMS-986120 is much lower than AYPGKF, suggesting high affinity of antagonist. Moreover, the electronegative aspartic residues Asp230 and Asp235 at ECL2 are important for PAR4 binding to agonist. Clarifying the PAR4 structural characteristics may be helpful to understand the activation mechanism, giving insights into the molecular design and discovery of novel potential PAR4 antagonists in the future.

100 Deals associated with UDM-001651

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Phase 1	-	Bristol Myers Squibb Co.	-
Blood Platelet Disorders	Preclinical	Canada	University of Montréal	21 Jun 2022

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