Thrombosis|Inhibitors Agonists Modulators Antagonists|HmoBio.com

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Thrombosis is a crucial hemostatic process for maintaining blood volume (hemostasis) following injury, yet aberrant thrombosis can trigger pathological conditions including myocardial infarction and stroke. Therefore the initiation of thrombosis is tightly controlled under physiological conditions.

Mechanisms of Thrombosis and Hemostasis

Platelets are a central component of thrombosis and exhibit a rapid, exponential activation in the event of tissue damage. Produced in the bone marrow, platelets are anucleate cell fragments of megakaryocytes. Despite having no nucleus, platelets possess two different types of granules within the cytoplasm - alpha granules and dense granules - and also express a number of different receptors on their plasma membranes. Both alpha and dense granules contain a variety of bioactive mediators including ADP, calcium and 5-HT as well as growth factors such as platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1) and transforming growth factor (TGF) β1. Upon activation, platelets undergo degranulation; this releases granule contents into the surrounding environment and promotes the activation and aggregation of neighboring platelets.

Receptors present on the platelet plasma membrane include the purinergic (P2X) receptors P2X1, P2Y1 and P2Y12; the 5-HT receptor 5-HT2A; the thromboxane A2 (TXA2) receptor TP; and the protease-activated receptorsPAR1 and PAR4. Platelet signaling may also be activated by exposure to collagen via the glycoprotein receptor, GPVI. Key downstream mediators of these receptors include the plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), which is cleaved by phospholipase C to form inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 receptor (InsP3R) activation triggers the efflux of calcium ions from intracellular calcium stores such as the endoplasmic reticulum, leading to a rise in intracellular calcium and subsequent platelet aggregation through the activation of integrin receptors.

Agonist stimulation of platelets also initiates the production of arachidonic acid from membrane phospholipids in a reaction catalyzed by cytosolic phospholipase A2 (cPLA2). Arachidonic acid can be utilized by both cyclooxygenases (COX) to form prostaglandin H2 (PGH2), and also by lipoxygenases (LOX) to form the lipid mediator hydroperoxyeicosatetraenoic acid (HPETE). PGH2 is further metabolized to form prothrombotic eicosanoids including TXA2.

Cat. No.	Product Name	CAS No.	Information
H7004	AZD 6482	1173900-33-8	A potent, selective and ATP competitive PI3Kβ inhibitor with IC50 of 10 nM; dispalys weak activity over PI3Kδ/PI3Kα/PI3Kγ/DNA-PK (IC50=80/870/1090/420 nM); potently inhibits Akt(Ser 473) phosphorylation in adenocarcinoma MDA-MB-468 cells (IC50=40 nM); inhibits insulin-induced human adipocyte glucose uptake in vitro (IC50=4.4 uM).
H6765	UK-396082	400044-47-5	UK-396082 is a potent and selective inhibitor of activated thrombin-activatable fibrinolysis inhibitor (activated TAFI; TAFIa) with Ki of 10 nM; displays excellent selectivity over plasma carboxypeptidase N (>1,000-fold); exhibits antithrombotic efficacy in a rabbit model of venous thrombosis, yet has no effect on surgical bleeding in the rabbit; possesses excellent preclinical and clinical pharmacokinetic profile, and shows potential for the treatment of thrombosis and other fibrin-dependent diseases in humans.
H6606	PF-06282999	1435467-37-0	A potent, highly selective and irreversible inhibitor of myeloperoxidase (MPO) with Kinact/KI of 116000 M-1s-1; displays high selectivity for MPO over TPO and cytochrome P450 isoforms; shows excellent pharmacological and pharmacokinetic profile; orally active.
H5582	Dabigatran ethyl ester	429658-95-7	A reversible and selective, direct thrombin inhibitor (DTI) with Ki value of 4.5 nM; an anticoagulant agent used to prevent stroke with atrial fibrillation.
H5581	Dabigatran etexilate mesylate	872728-81-9	A prodrug of BIBR-953, which is a potent nonpeptide thrombin inhibitor with Ki of 4.5 nM; 10-fold less potent for Trypsin and no activity against Factor Xa, Plasmin, tPA and activated protein C; exhibits strong and long-lasting anticoagulant effects ex vivo and strong oral activity in different animal species.
H5580	Dabigatran etexilate	211915-06-9	A prodrug of BIBR-953, which is a potent nonpeptide thrombin inhibitor with Ki of 4.5 nM; 10-fold less potent for Trypsin and no activity against Factor Xa, Plasmin, tPA and activated protein C; exhibits strong and long-lasting anticoagulant effects ex vivo and strong oral activity in different animal species.
H5464	XR 5118	174766-49-5	XR 5118 is a small molecule plasminogen activator inhibitor-1 (PAI-1) inhibitor with IC50 of 3.5 uM, binds to PAI-1 and reduces plasma PAI-1 activity levels, promotes endogenous thrombolysis and inhibits thrombus accretion; the first nonpeptide compound with significant anti-PAI-1 activity in vivo.
H5134	Rivaroxaban	366789-02-8	A highly potent and selective, direct FXa inhibitor with IC50 of 0.7 nM; displays >10,000-fold greater selectivity than for other serine proteases, also inhibits prothrombinase activity (IC50=2.1 nM); inhibits endogenous FXa more potently in human than rat plasma (IC50 21 nM vs 290 nM); reduces venous thrombosis dose dependently (ED50=0.1 mg/kg i.v.) in a rat venous stasis model; orally active.
H5133	Razaxaban hydrochloride	405940-76-3	A highly potent, selective, and orally bioavailable factor Xa (FXa) inhibitor with Ki of o.19 nM, >5,000-fold selectivity over a series of related serine proteases; inhibits thrombus formation in a dose-dependent manner with an ID50 of 1.6 ¦Ìmol kg-1 h-1 in rabbit arterio-venous shunt thrombosis model.
H5132	Razaxaban	218298-21-6	A highly potent, selective, and orally bioavailable factor Xa (FXa) inhibitor with Ki of o.19 nM, >5,000-fold selectivity over a series of related serine proteases; inhibits thrombus formation in a dose-dependent manner with an ID50 of 1.6 ¦Ìmol kg-1 h-1 in rabbit arterio-venous shunt thrombosis model.

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