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

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

Defect in Sensing Human Thrombin by Porcine Endothelial Protease-Activated Receptor-1: Molecular Incompatibility Between Porcine PAR-1 and Human Thrombin. (PubMed, Xenotransplantation) - "Additionally, experiments using the PAR-1 inhibitor vorapaxar (Vor) show that inhibiting PAR-1 signaling can suppress inflammatory cytokine and chemokine expression in co-cultures of human macrophages and porcine endothelial cells. These findings suggest that selective PAR-1 inhibitors or targeted therapies regulating thrombin-PAR-1 signaling may improve the success rate of xenotransplantation. However, further in vivo studies are needed to validate these findings and explore therapeutic interventions targeting thrombin-PAR-1 interactions to enhance xenograft survival."

Journal • Preclinical • Inflammation • Transplantation

Efficacy and safety of antiplatelet therapy for secondary prevention of small subcortical infarction: A systematic review and network meta-analysis. (PubMed, Eur Stroke J) - "Cilostazol may be the most effective agent for preventing cardiovascular event recurrence. Aspirin plus clopidogrel and vorapaxar may be not recommended due to heightened bleeding risks."

Journal • Retrospective data • Review • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Ischemic stroke

Dual inhibition of canonical and noncanonical PAR-1 by SCH79797 mitigates neurodegeneration in 3-NP-induced Huntington's disease: An in vivo and in silico approach. (PubMed, Arch Pharm (Weinheim)) - "In silico study showed better blood-brain barrier (BBB) diffusion by SCH79797 than by vorapaxar...SCH79797 inhibited apoptosis, by reducing caspase-3 and cytochrome C, and increased voltage-dependent anion channel-1 (VDAC1) to maintain mitochondrial function. Overall, SCH79797 inhibited PAR-1 canonically and noncanonically to counter excitotoxicity, oxidative stress, inflammation, apoptosis, and mitophagy, thereby preserving BBB and mitochondrial integrity, improving histological outcomes, and enhancing behavioral performance."

Journal • Preclinical • CNS Disorders • Huntington's Disease • Inflammation • Movement Disorders • Oncology • Targeted Protein Degradation • CASP3 • CLDN5 • MMP1 • MMP9 • PTEN • TNFA • VDAC1

Targeting PAR1 activation in JAK2V617F-driven philadelphia-negative myeloproliferative neoplasms: Unraveling its role in thrombosis and disease progression. (PubMed, Neoplasia) - "We investigated the effects of thrombin, a PAR1 antagonist (vorapaxar), and a JAK2 inhibitor (ruxolitinib) on Ph-MPN cells. This study highlights that elevated PAR1 expression in primitive hematopoietic subpopulations is linked to disease progression and thrombosis in Ph-MPNs, suggesting PAR1 as a potential therapeutic target. Combining PAR1 antagonists with JAK2 inhibitors shows promise in reducing PAR1 expression and mitigating thrombotic events in Ph-MPN patients."

Journal • Cardiovascular • Hematological Disorders • Myeloproliferative Neoplasm • Oncology • Thrombosis • CD34

Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study). (PubMed, JACC Adv) - "L-citrulline and, when ADMA levels are pathological, H4Bip are effective nutritional interventions in patients with PAD warranting further confirmatory trials."

Journal • P2 data • Cardiovascular • Peripheral Arterial Disease

Activation of PAR1 contributes to ferroptosis of Schwann cells and inhibits regeneration of myelin sheath after sciatic nerve crush injury in rats via Hippo-YAP/ACSL4 pathway. (PubMed, Exp Neurol) - "Inhibition of PAR1 can relieve ferroptosis after sciatic nerve crush injury in SD rats through Hippo-YAP/ACSL4 pathway, thereby regulating myelin regeneration after injury. In summary, PAR1/Hippo-YAP/ACSL4 pathway may be a promising therapeutic target for promoting functional recovery post-sciatic crush injury."

Journal • Preclinical • ACSL4 • YAP1

Efficacy and Safety of Vorapaxar in Patients with Peripheral Arterial Disease: A Meta-Analysis of Randomized Controlled Trials (AHA 2024) - "In patients with PAD, Vorapaxar significantly reduces hospitalizations due to acute limb ischemia and the need for peripheral revascularizations compared to placebo. However, it does not have a significant effect on the need for lower extremity amputations. In terms of safety, Vorapaxar does not lead to fatal or severe bleedings compared to placebo."

Retrospective data • Cardiovascular • Peripheral Arterial Disease

Differential Effect of Omega-3 Fatty Acids on Platelet Inhibition by Antiplatelet Drugs In Vitro. (PubMed, Int J Mol Sci) - "The antiplatelet drugs aspirin and triflusal, inhibitors of cyclooxygenase-1 (COX-1); ticagrelor, an inhibitor of the receptor P2Y12; vorapaxar, an inhibitor of the PAR-1 receptor, were combined with DHA or EPA and evaluated against in vitro platelet aggregation induced by agonists arachidonic acid (AA), adenosine diphosphate (ADP) and TRAP-6. We further investigated procaspase-activating compound 1 (PAC-1) binding and P-selectin membrane expression in platelets stimulated with ADP and TRAP-6...The antiplatelet drugs exhibited heterogeneity regarding their effect on P-selectin and αIIbβ3 membrane expression, while both omega-3 PUFAs inhibited the membrane expression of αIIbβ3, though had no effect on P-selectin expression induced by ADP or TRAP-6. The combinatory effect of DHA and EPA with the antiplatelet drugs did not result in enhanced inhibitory activity compared to the sum of the individual effects of each component."

Journal • Preclinical • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Inflammation • Metabolic Disorders

PAR1 Inhibition Vorapaxar as a Potential Therapeutic Approach in Chronic Thromboembolic Pulmonary Hypertension (ERS 2024) - "Furthermore, after administering vorapaxar for 7 days, we observed a significant reduction in thrombus mass and volume (P = 0.002, N = 10), and the vorapaxar group exhibited faster dissolution of thrombi over time compared to the control group. Conclusion(s) In conclusion, we have found that PAR1 plays a significant role in the progression of CTEPH and the PAR1 inhibitor vorapaxar shows potential efficacy in inhibiting thrombus dissolution."

Cardiovascular • Pulmonary Arterial Hypertension • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases • Thrombosis

Biochemical and biophysical characterization of Leishmania donovani citrate synthase. (PubMed, Int J Biol Macromol) - "Enzyme inhibition assays revealed that LdCS activity is competitively inhibited by FDA-approved compounds-Abemaciclib, Bazedoxifene, Vorapaxar, and Imatinib-with Ki values ranging from 2 to 3 μM, demonstrating significant binding affinity. This research paves the way for exploring LdCS as a potential drug target for treating leishmaniasis."

Journal • Infectious Disease