Zontivity (vorapaxar) / Merck (MSD) - LARVOL DELTA

Protease-activated receptor 1 in diabetes and its chronic complications: signaling mechanisms and emerging therapeutic advances. (PubMed, Front Pharmacol) - "This review also outlines recent advances in PAR1-targeted therapies, including orthosteric antagonists such as vorapaxar, biased signaling modulators such as 3K3A-APC and parmodulins, and intracellular inhibitors such as PZ-128. Their therapeutic potential and current challenges in antithrombotic therapy and target-organ protection are also discussed, with the aim of informing more precise strategies for preventing and treating DM and its chronic complications."

Journal • Review • Cardiovascular • Diabetes • Diabetic Nephropathy • Diabetic Neuropathy • Diabetic Retinopathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Pain • Renal Disease • Retinal Disorders • Type 2 Diabetes Mellitus

Platelet-Derived Cathepsin G/MMP9-Mediated PAR1 Activation Governs Thrombolysis in Chronic Thromboembolic Pulmonary Hypertension (ERS 2026) - "Protease-activated receptor 1 (PAR1) is involved in thrombosis-related pathological processes, but its role and regulatory mechanism in CTEPH thrombolysis remain unclear. Through animal experiments (inferior vena cava thrombosis model), cell co-culture, single-cell sequencing, proteomics and other techniques, the expression of PAR1 (endothelial cell localization) in CTEPH and healthy individuals, and the PAR1-activating molecules secreted by platelets (cathepsin G, MMP9) were analyzed, and the effects of PAR1 inhibitors (Vorapaxar) and gene knockout on thrombolysis were verified... PAR1 regulates the phenotype of CTEPH endothelial cells through cathepsin G and MMP9 secreted by platelets. Inhibiting PAR1 can accelerate thrombolysis, providing a new target for thrombosis intervention in CTEPH."

Cardiovascular • Hematological Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases • Thrombosis • CTSG • MMP9

Platelet reactivity in polymorbid older patients and the effect of 4-methylcatechol. (PubMed, BMC Geriatr) - "The ex vivo response of platelets from PP to the standard antiplatelet drugs was lower. In contrast, they responded well to 4-methylcatechol."

Journal • Cardiovascular • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

PAR1 Inhibition Accelerates Thrombolysis in CTEPH by Targeting Endothelial Cell Phenotype Regulated by Platelet Secretory Factors (ISTH 2026) - "The effects of PAR1 inhibitor (Vorapaxar) and PAR1 gene knockout on thrombolysis were further validated...Inhibition of PAR1 can accelerate thrombolysis, thereby providing a novel target for thrombosis intervention in CTEPH. Table or Figure Upload (1) Page 2 DOI*10.1016/j.rpth.2026.106309"

Cardiovascular • Hematological Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases • Thrombosis • CTSG • MMP9

The birth of a new ex-vivo haemostasis model (ISTH 2026) - "Haemostasis was assessed ex-vivo in placental vessels perfused in-situ with donor blood, by measuring bleeding time following needlestick injuries (300µm) in the presence of rivaroxaban, vorapaxar, cangrelor or Glenzocimab. Conclusions Placental vessels offer a viable option to develop ex-vivo models of human thrombosis and haemostasis, with the potential to reduce animal usage and improve translation of results. DOI*10.1016/j.rpth.2026.105196"

Preclinical • Cardiovascular • Hematological Disorders • Thrombosis

Gestodene Accelerates Cutaneous Wound Healing via PAR1-Selective Positive Allosteric Modulation. (PubMed, Int J Mol Sci) - "In a murine wound model, topical administration of gestodene accelerated wound closure, achieving complete re-epithelialization by Day 8 and significantly enhancing collagen deposition, effects reversed by vorapaxar. Collectively, these findings demonstrate that gestodene accelerates cutaneous wound healing through PAR1-selective positive allosteric modulation and supports its potential as a drug repositioning candidate for wound repair."

Journal • COL1A1 • MMP1

Vorapaxar utilization and cost trends in US public insurance programs. (PubMed, Vasc Med) - No abstract available

Journal • Reimbursement • US reimbursement • Cardiovascular • Hematological Disorders • Peripheral Arterial Disease • Thrombosis

Analysis and mining of adverse events associated with vorapaxar: A FAERS database-based study. (PubMed, PLoS One) - "The adverse events involved 19 organ systems. Reports on vascular diseases, neurological diseases, and other conditions were numerous with strong signals, which were consistent with the drug instructions. Among them, vascular diseases had the highest risk of positive signals, including various hemorrhagic events and vascular structural/functional abnormalities. These findings suggest that clinical practice should be alert to adverse reactions in the vascular system, especially bleeding and severe vascular structural abnormalities."

Adverse events • Journal • Cardiovascular • CNS Disorders • Hematological Disorders

Understanding how a highly prevalent GRK5 polymorphism affects platelets and enhances thrombotic risk. (PubMed, Blood) - "Under venous shear in an endothelialized microfluidic system, GG platelets exhibited increased accumulation, which was reversed by PAR1 inhibition with vorapaxar...This study provides the first experimental evidence directly linking a highly prevalent human GRK5 variant to defective PAR1 regulation and increased thrombotic risk. Together, these findings establish that the GRK5 GG genotype confers increased thrombotic potential through impaired PAR1 desensitization, providing mechanistic insight that connects human genetics, thrombin receptor signaling, and thrombotic disease."

Journal • Cardiovascular • Hematological Disorders • Venous Thromboembolism

PlateChek: A Surface-functionalized Dielectric Microsensor for Specific Detection of Platelet-related Hemostatic Impairment in Whole Blood. (PubMed, J Thromb Haemost) - "PlateChek is a novel whole blood-based coagulometer with translational potential that directly correlates both platelet count and function defects to hemostatic impairment."

Journal • Hematological Disorders • Thrombocytopenia

Identification of novel gene expression programs in thrombin-stimulated hepatic stellate cells. (PubMed, Res Pract Thromb Haemost) - "In some experiments, cells were pretreated with the PAR1 antagonist, vorapaxar (0.01-10 μM)...These results show that thrombin alters previously unidentified transcriptomic profiles, suggesting a program toward HSC activation. Thrombin activates complex signaling pathways for HSC preinitiation, which may drive HSC activation and hepatic fibrosis."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis

Cathepsin G Potentiates Biased Signaling through Protease Activated Receptor 4 (ASH 2024) - "We used PAR-specific inhibitors, BMS-986120 (PAR4) and vorapaxar (PAR1) to show specificity of signaling...In comparison to AYPGKF, CatG modestly increases calcium flux while RALL-11mer fails to elicit a calcium response. Since calcium mobilization is a critical step in both degranulation and integrin activation, this provides a potential mechanism for how CatG potentiates biased signaling through PAR4."

Cardiovascular • Venous Thromboembolism • CTSG

Phenotyping of human platelets in response to platelet agonists and inhibitors using multiparameter flow cytometry and unbiased high-dimensional analysis. (PubMed, Res Pract Thromb Haemost) - "To determine how inhibitors affect platelet subpopulations, WB was pretreated with prostacyclin, dasatinib, vorapaxar, or ticagrelor prior to stimulation with adenosine diphosphate, thrombin receptor-activating peptide-6, or convulxin. Platelet subpopulations are dynamic and undergo remodeling in response to different agonists and inhibitors. This high-dimensional single-cell flow cytometry assay is a practicable approach to evaluate the effects of agonists and inhibitors on platelet receptor expression and platelet subpopulations."

Journal • BSG • CD36 • CD40LG • CD63 • CXCR4 • FCGR2A • SCARB1 • SELP

Stochastic resonance represents one of the mechanisms that trigger protein ligand unbinding. (PubMed, J Mol Graph Model) - "The unbinding of the Vorapaxar (VPX) from the β-sheet of the Endothelial cell Protein C Receptor (EPCR) can be observed during a 100 ns unbiased Molecular Dynamics simulation while VPX in the hydrophobic cleft remained in a bound state during a microsecond-long simulation...The mEPCR, which has lower frequencies of normal modes than sEPCR, could afford the resonant conditions for both temperatures. Thus, ligand unbinding in the EPCR-VPX model was triggered by enhanced vibrations induced by the stochastic resonance."

Journal • PROCR

SCH79797, an Antiplatelet Agent, Alleviates Restenosis by Inducing Apoptosis via p53-Mediated Mitochondrial Depolarization and Inhibiting Thrombus Formation after Angioplasty. (PubMed, Curr Mol Med) - "Our findings have established SCH79797 as a promising candidate for reducing ISR through apoptosis modulation. By leveraging the p53-mediated mitochondrial apoptotic pathway, SCH79797 may provide a groundbreaking approach to reducing restenosis. These findings could offer significant implications for the future development of targeted drug-eluting strategies by locally delivering SCH79797 in a controlled manner using DES or DEB, presenting SCH79797 as a transformative candidate in interventional cardiology."

Journal • Cardiovascular • Hematological Disorders • Thrombosis • BAX • BCL2

Validation and translation of therapeutic potential of thrombin-PAR1 signaling in suppressing fibrosis using microphysiological PDAC tumor models Free (AACRPanCa 2025) - "Furthermore, pharmacological inhibition of PAR1 by vorapaxar decreases both PCC and CAFs in all human PCC/CAF pairs studied...In summary, we validate and translate the therapeutic potential of thrombin-PAR1 signaling in reprogramming PDAC stroma using novel MPS of PDAC tumor-stroma model. Our study also demonstrates MPS as a promising system for target identification, validation, and streamlining preclinical studies for drug discovery."

Preclinical • Fibrosis • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs

Vorapaxar enhanced mitochondria-associated ferroptosis primes cancer immunotherapy via targeting FOXO1/HMOX1 axis. (PubMed, Cell Rep Med) - "Clinically, high FOXO1/HMOX1 co-expression correlates with improved immunotherapy response and progression-free survival. These findings position vorapaxar as a promising adjunct to immunotherapy, offering a dual benefit for cancer patients requiring both antithrombotic therapy and immunotherapy."

IO biomarker • Journal • Cardiovascular • Hematological Disorders • Melanoma • Oncology • Solid Tumor • BRAF • FOXO1 • HMOX1 • PTEN

Integrative snRNA-seq, molecular docking and dynamics simulations identifies Lasmiditan as drug candidate for Alzheimer's disease. (PubMed, Clin Transl Med) - "20 key transcriptional regulators (DERs) were identified linked to AD in myeloid, and neuronal cell populations. The DERs correlated with Braak stage, APOE genotype, and aging. ETV6 is a potentially viable therapeutic target due to its ability to form stable and strongly interacting complexes across multiple drugs. Lasmiditan showed the strongest binding to ETV6 (RMSD: 2.98 Å, H-bonds: 68.38) and optimal blood-brain-barrier (BBB) penetration (LogP 3-4, TPSA 60-75). Lasmiditan is a potentially promising AD therapeutic candidate that warrants further preclinical validation."

Journal • Alzheimer's Disease • CNS Disorders • APOE • ETV6 • PAX6 • ZEB2

Acetylsalicylic acid and vorapaxar are less active, while 4-methylcatechol is more active, in type 1 diabetic patients compared to healthy controls. (PubMed, Cardiovasc Diabetol) - "Conclusively, 4-methylcatechol seems to be a prototypical antiplatelet compound with a strong effect even in diabetic patients."

Clinical • Journal • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

High salt diet intake promotes the induction of experimental autoimmune encephalomyelitis by exacerbating neutrophil infiltration and microglial activation. (PubMed, Eur J Pharmacol) - "The HS diet-induced exacerbation of clinical scores and microglial activation were improved by the pharmacological inhibition of neutrophil chemotaxis with SB225002, a selective CXC chemokine receptor 2 inhibitor. In addition, the pharmacological inhibition of microglial activation with minocycline markedly ameliorated clinical scores of HS diet-fed EAE mice...Blockade of thrombin signaling with vorapaxar, a selective blocker of PAR-1, significantly improved EAE symptoms in the HS diet group. Collectively, our findings suggest that excessive salt intake promotes EAE induction via the activation of neutrophils and microglia in the spinal cord. Dietary salt restriction might be a promising strategy to prevent developing or relapsing MS."

Journal • CNS Disorders • Immunology • Multiple Sclerosis • Solid Tumor

Identification of novel gene expression programs in thrombin-stimulated hepatic stellate cells (ISTH 2025) - "Pathway analysis and gene set enrichment analysis revealed upregulation of genes involved in epithelial-mesenchymal transition and TNF signaling, and downregulation of cholesterol homeostasis with 4h thrombin treatment. Interestingly, induction of genes (e.g., CALD1, SERPINE1) from key pathways in thrombin-stimulated LX2 was blocked by vorapaxar pre-treatment."

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • ACTA2 • COL1A1 • SERPINE1

Differential regulation of cAMP by PDE3 discriminates PAR1 and PAR4 signaling (ISTH 2025) - "Washed human platelets were pre-incubated with a PAR1 or PAR4 inhibitor (Vorapaxar or BMS-986120, respectively) before thrombin stimulation...Since PDE3A regulates cAMP levels, we examined if PAR1 controls PDE3A activation. Inhibition of PDE3A with an inhibitor or through genetic deletion, reversed the PAR1-induced decrease in cAMP levels, while PAR4 signaling was not affected by PDE3A inhibition."

CD34 • PDE3A

Human PAR1 expressed on mouse platelets contributes to hemostasis and arterial occlusion. (PubMed, bioRxiv) - "The specific hPAR1 antagonist drug, vorapaxar reverses the phenotypic changes associated with hPAR1 expression in PAR3 -/- mice expressing mouse PAR4. Experimental data from PAR3 -/- mice expressing hPAR1 should be directly relevant to the development of specific thrombin-induced platelet activation inhibitors."

Journal • Preclinical • PARD3

Molecular Dynamics-Guided Repositioning of FDA-Approved Drugs for PD-L1 Inhibition with In Vitro Anticancer Potential. (PubMed, Int J Mol Sci) - "From this screening, five promising compounds-vorapaxar, delafloxacin, tenofovir disoproxil, pivmecillinam, and fursultiamine-showed significant binding affinities to PD-L1 and demonstrated cytotoxic activity against A549 lung tumor cells. These findings suggest that pivmecillinam has promising immunomodulatory potential and could serve as a candidate for further development in cancer immunotherapy. Overall, this study underscores the value of integrating high-throughput MD and experimental approaches for drug repositioning to identify novel therapeutic agents."

FDA event • Journal • Preclinical • Lung Cancer • Oncology • Solid Tumor

PAR1 inhibition sensitizes HPV-negative HNSCC cells to ferroptosis through inhibition of the STAT3-mediated regulation of iron and lipid metabolic pathways. (PubMed, Oncogene) - "It is worth noting that the PAR1 small molecule inhibitor Vorapaxar can further enhance the therapeutic effect of Erastin on HPV-negative HNSCC. Therefore, we propose that PAR1 participates in the progression of HPV-negative HNSCC through STAT3 and reduces the sensitivity of HPV-negative HNSCC to ferroptosis, providing a new perspective for discovering ferroptosis regulatory factors."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • GPX4 • SLC7A11 • STAT3