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

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

doi:10.1021/acs.jmedchem.2c00359

Cited by 17 publications

(14 citation statements)

References 31 publications

(63 reference statements)

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“…28,37,38 In fact, the increased risk of bleeding resulting from inhibition of PAR1 in humans has led to considerable interest in the development and characterization of PAR4-specific antagonists for their antithrombotic activity, with reports suggesting that they may be well tolerated in humans. 34–36,54,55 This may suggest potential clinical benefit for PAR4 antagonism in humans. Clinical utility, however, remains to be demonstrated for PAR4 antagonism and for RAG8, specifically.…”

Section: Discussionmentioning

confidence: 99%

“…32,33 This has prompted renewed interest in the development of PAR4 antagonists as potential antithrombotic agents. [34][35][36] Mouse platelets express PAR3 and PAR4, with PAR4 representing the major receptor for thrombin-mediated platelet activation. 37,38 We previously identified an intracellular motif on the PAR4 C terminus (RAGLFQRS) that coordinately regulates calcium signaling and interaction of the receptor with β-arrestins 1 and 2.…”

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confidence: 99%

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PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice

Lee,

Malik,

Zhou

et al. 2023

ATVB

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BACKGROUND: SR-B1 (scavenger receptor class B type 1)/LDLR (low-density lipoprotein receptor) double knockout mice fed a high-fat, high-cholesterol diet containing cholate exhibit coronary artery disease characterized by occlusive coronary artery atherosclerosis, platelet accumulation in coronary arteries, and myocardial fibrosis. Platelets are involved in atherosclerosis development, and PAR (protease-activated receptor) 4 has a prominent role in platelet function in mice. However, the role of PAR4 on coronary artery disease in mice has not been tested. METHODS: We tested the effects of a PAR4 inhibitory pepducin (RAG8) on diet-induced aortic sinus and coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis in SR-B1/LDLR double knockout mice. SR-B1/LDLR double knockout mice were fed a high-fat, high-cholesterol diet containing cholate and injected daily with 20 mg/kg of either the RAG8 pepducin or a control reverse-sequence pepducin (SRQ8) for 20 days. RESULTS: Platelets from the RAG8-treated mice exhibited reduced thrombin and PAR4 agonist peptide–mediated activation compared with those from control SRQ8-treated mice when tested ex vivo. Although aortic sinus atherosclerosis levels did not differ, RAG8-treated mice exhibited reduced coronary artery atherosclerosis, reduced platelet accumulation in atherosclerotic coronary arteries, and reduced myocardial fibrosis. These protective effects were not accompanied by changes in circulating lipids, inflammatory cytokines, or immune cells. However, RAG8-treated mice exhibited reduced VCAM-1 (vascular cell adhesion molecule 1) protein levels in nonatherosclerotic coronary artery cross sections and reduced leukocyte accumulation in atherosclerotic coronary artery cross sections compared with those from SRQ8-treated mice. CONCLUSIONS: The PAR4 inhibitory RAG8 pepducin reduced coronary artery atherosclerosis and myocardial fibrosis in SR-B1/LDLR double knockout mice fed a high-fat, high-cholesterol diet containing cholate. Furthermore, RAG8 reduced VCAM-1 in nonatherosclerotic coronary arteries and reduced leukocyte and platelet accumulation in atherosclerotic coronary arteries. These findings identify PAR4 as an attractive target in reducing coronary artery disease development, and the use of RAG8 may potentially be beneficial in cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice

Lee,

Malik,

Zhou

et al. 2023

ATVB

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“…Detailed SAR studies and design of conformationally constrained cores led to the discovery of a series of novel quinoxaline-benzothiazole PAR4 antagonists with potent activity against PAR4 activation induced by both PAR4 AP and γ-thrombin. previously reported clinical candidate BMS-986120 17 and represents a potent antagonist from a distinct chemical series, providing an additional valuable tool against a target with sparsely reported small-molecule modulators.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…16 Recently, a small-molecule PAR4 antagonist, BMS-986120 (Figure 1), has been reported to demonstrate outstanding efficacy and bleeding profile in cynomolgus monkey models, providing impetus for continued optimization of PAR4 antagonists. 16,17 The unique activation mechanism of PARs has posed a challenge for the development of clinically useful antagonists. In particular, PAR activation by thrombin is a highly efficient and irreversible process, and the tethered ligand generated by thrombin cleavage is difficult to inhibit because of its high effective concentration (intramolecular ligand).…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis

Zhang,

Jiang,

Richter

et al. 2024

J. Med. Chem.

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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 IC 50 against PAR4 activation by γthrombin 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.

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“…142 In monkey models, the selective PAR4 inhibitors, BMS-986120 and BMS-986141, demonstrated antithrombotic efficacy with a minimal increase in bleeding time, when compared to clopidogrel; these compounds are now further developed. 143 In addition, CLEC-2 is on the list of targetable receptors due to its role in thrombo-inflammation, cancer and metastasis. However, no anti-CLEC-2 drug is currently available for clinical use.…”

Section: Antiplatelet Therapiesmentioning

confidence: 99%

Novel platelet glycoprotein VI and CLEC-2 targeting strategies

Navarro¹

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Glycoprotein (GP)VI is the major platelet collagen receptor and a promising antithrombotic target. This was first demonstrated in mice using the rat monoclonal antibody JAQ1, which completely blocks the collagen-related peptide (CRP)-binding site on mouse GPVI and efficiently inhibits mouse platelet adhesion, activation and aggregation on collagen. Here, we show for the first time that JAQ1 cross-reacts with human GPVI (huGPVI), but not with GPVI in other tested species, including rat, rabbit, guinea pig, swine, and dog. We further demonstrate that JAQ1 differently modulates mouse and human GPVI function. Similar to its effects on mouse GPVI (mGPVI), JAQ1 inhibits CRP-induced activation in human platelets, whereas, in stark contrast to mouse GPVI, it does not inhibit the adhesion, activation or aggregate formation of human platelets on collagen, but causes instead an increased response. This effect was also seen with platelets from newly generated human GPVI knock-in mice (hGP6tg/tg).These results indicate that the binding of JAQ1 to a structurally conserved epitope in GPVI differently affects its function in human and mouse platelets.

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

Cited by 17 publications

References 31 publications

PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice

PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice

Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis

Novel platelet glycoprotein VI and CLEC-2 targeting strategies

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