title: Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding.
abstract: Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. pancras.wong@bms.com.
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, NJ 08543, USA.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seiffert
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: J Eileen
authors.initials: JE
authors.lastname: Bird
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Watson
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bostwick
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Giancarli
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Allegretto
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Hua
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: David
authors.initials: D
authors.lastname: Harden
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Guay
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Callejo
authors.affiliation: Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, NJ 08543, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Miller
authors.affiliation: Bristol-Myers Squibb Company, 350 Carter Road, Hopewell, NJ 08540, USA.
authors.forename: R Michael
authors.initials: RM
authors.lastname: Lawrence
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Banville
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Guy
authors.affiliation: Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, NJ 08543, USA.
authors.forename: Brad D
authors.initials: BD
authors.lastname: Maxwell
authors.affiliation: Bristol-Myers Squibb Company, 350 Carter Road, Hopewell, NJ 08540, USA.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Marinier
authors.affiliation: Bristol-Myers Squibb Company, 350 Carter Road, Hopewell, NJ 08540, USA.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec H3C 3J7, Canada.|Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Quebec H3C 3J7, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Gordon
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.affiliation: Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001792:Blood Platelets / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006470:Hemorrhage / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D008252:Macaca fascicularis; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D000072417:Protein Domains; D044463:Receptor, PAR-1 / Q000378:metabolism; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D020521:Stroke / Q000188:drug therapy; D013917:Thrombin / Q000737:chemistry; D013927:Thrombosis; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D013917:Thrombin; C112908:protease-activated receptor 4