The Discovery of Vorapaxar (SCH 530348), a Thrombin Receptor (Protease Activated Receptor-1) Antagonist with Potent Antiplatelet Effects - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 28

Table 2.1 Classification of major marketed antithrombotic agents.
Name

Mechanism of action Formulation

Anticoagulants
Warfarin Vitamin K antagonist Oral

Heparin, Danaparoid, Dalte-
parin, Tinzaparin, Enoxaparin,
Fondaparinux

Antithrombin cofactor iv or sc

Lepirudin, Bivaluridin,
Argatroban

Direct thrombin inhibitors iv

Rivaroxaban Factor Xa inhibitor Oral

Antiplatelet agents
See Table 2.2
Fibrinolytic agents
Streptokinase, Alteplase,
Tenectaplase, Reteplase

Promote plasmin activity iv

interact with sub-endothelial collagen, which causes their activation. Activation
of platelets prompts cytoskeletal rearrangements, membrane fusion, exteriza-
tion, and internal synthesis and release of thromboxane A2 (TxA 2 ), which itself
is a potent platelet activator. Secretion of platelet granular contents releases a
variety of biochemical agonists—such as adenosine diphosphate (ADP) and
serotonin—that further activate platelets by interacting with their specific
platelet surface receptors (Figure 2.1). 26,27 Additionally, thrombin that is
locally generated at the site of injury activates platelets via protease-activated
receptors (PARs). 28
Among the various platelet stimulants, thrombin is the most potent activator
of platelets. 29 Vascular injury and inflammation expose tissue factor, resulting
in the formation tissue factor/factor VIIa complex that leads to the local
generation of thrombin from prothrombin. Platelets also facilitate thrombin
generation by providing procoagulant phospholipid surfaces that anchor
various coagulation factors. Thrombin activates platelets at very low con-
centrations by interacting with PARs.
Activation of platelets and the ensuing intracellular biochemical events lead
to the activation of surface GP IIb/IIIa receptors—the final, convergent
pathway in the platelet activation mechanism. GP IIb/IIIa is a member of the
integrin family of receptors, composed of a- and b-subunits (a IIb , b 3 ). In the
resting state, platelet GP IIb/IIIa receptors do not bind to fibrinogen (or bind
with a very low anity). 30 Activation alters the conformation of GP IIb/IIIa,
rendering itself capable of binding to extracellular macromolecular ligands,
including fibrinogen and von Willebrand Factor (vWF). The arginine-glycine-
aspartic acid (RGD) sequence of the adhesive proteins binds to the GP IIb/IIIa
receptor. Fibrinogen contains two RGD sequences on its a-chain, one in the N-
terminal region and the other in the C-terminal region, and is therefore bivalent
in its binding to GP IIb/IIIa receptors, which allows ecient cross-linking of
platelets. 31 Although vWF also binds to the GP IIb/IIIa receptor at its various
RGD sites, studies in fibrinogen knockout mice have shown that vWF alone is
not sucient to achieve stable platelet aggregation. 32