3P-0836 Biological characterization of ER129614-06, a novel, non-peptide protease-activated receptor-1 (PAR-1) antagonist

Kogushi, Motoji; Matsuoka, Takuma; Kobayashi, Haruo; Sato, Nobuhiro; Kawahara, Teppei; Kajiwara, Atsushi; Hishinuma, Ieharu

doi:10.1016/s1567-5688(03)91054-3

Cited by 5 publications

(4 citation statements)

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“…Optimization of urea-based antagonists included reducing the piperidine ring size and a hydroxyl group on the ring that may act as a hydrogen bond donor and/or acceptor with PAR1 [191]. An iminoisoindoline derivative ER129614-06 (IC 50 14 nM vs thrombin and 28 nM vs SFLLRN, Figure 6) was then discovered as a very potent PAR1 antagonist that shows anti-thrombotic effect in a dose-dependent manner with good oral bioavailability in guinea pig thrombosis model [192]. Compounds based on piperazine, F16357 and F16618 (Figure 6), were developed as PAR1 selective antagonists that inhibit >90% intracellular Ca 2+ release at 10 μM [193].…”

Section: Accepted Articlementioning

confidence: 99%

“…An iminoisoindoline derivative ER129614‐06 (IC 50 14 n m vs thrombin and 28 n m vs SFLLRN, Fig. 6) was then discovered as a very potent PAR1 antagonist that shows antithrombotic effect in a dose‐dependent manner with good oral bioavailability in guinea pig thrombosis model [191]. Compounds based on piperazine, F16357 and F16618 (Fig.…”

Section: Synthetic Pars Modulators and Structure–activity Relationshipmentioning

confidence: 99%

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Molecular mechanisms regulating Proteinase‐Activated Receptors (PARs)

Chandrabalan

Ramachandran

2021

The FEBS Journal

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Proteinase activated receptors (PARs) are a four-member family of G protein-coupled receptors defined by their irreversible proteolytic mechanism of activation. PARs have emerged as important regulators of various physiological responses and are implicated in numerous pathological conditions. Importantly, PAR1 and PAR4 are critical regulators of platelet function, while PAR2 is well established as a driver of inflammatory responses. PAR targeted drug development efforts are therefore of great interest. In this review, we provide an overview of recent advances in our understanding of molecular mechanisms underlying PAR activation, effector interaction and signalling. We also provide an overview of the diverse proteolytic enzymes that are now established as PAR regulators and describe the ability of different enzymes to elicit biased signalling through PARs. Finally, we highlight recent advances in the development of PAR targeted pharmacological agents and discuss recent structure-activity relationship studies.

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Section: Accepted Articlementioning

confidence: 99%

Section: Synthetic Pars Modulators and Structure–activity Relationshipmentioning

confidence: 99%

Molecular mechanisms regulating Proteinase‐Activated Receptors (PARs)

Chandrabalan

Ramachandran

2021

The FEBS Journal

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“…In the radioligand binding assay, this compound showed an IC 50 of 19 nM. It inhibited TRAP-induced human and guinea pig platelet-rich plasma (PRP) aggregations with IC 50 values of 31 and 97 nM, respectively [350,351]. It also inhibited thrombin-induced human and guinea pig PRP aggregations with IC 50 values of 64 and 130 nM, respectively.…”

Section: Peptidomimetic Thrombin Receptor Antagonistsmentioning

confidence: 99%

Antiplatelet Agents

Chackalamannil¹

2010

Burger's Medicinal Chemistry and Drug Discovery

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In addition to their life‐sustaining role in hemostasis and wound healing, platelets play a central role in the pathogenesis of coronary artery, cerebrovascular, and peripheral vascular diseases. Under pathologic conditions such as rupture of an atherosclerotic plaque, the platelet activation mechanism and coagulation mechanism synergize in the formation of an occlusive thrombus leading to ischemic disorders such as acute coronary syndrome and stroke. Antiplatelet agents are the mainstay of pharmacological approach for the treatment of ischemic vascular disorders. Platelets have multiple cell‐surface receptors that, upon activation by specific ligands, trigger a cascade of cellular events resulting in the activation of the integrin glycoprotein (GP) IIb/IIIa receptors. Activated GP IIb/IIIa receptors cross‐link with fibrinogen causing platelet to aggregate. Aggregated platelets get trapped by fibrin meshwork, produced by the proteolysis of fibrinogen by thrombin. Cell‐surface platelet receptors have been the target of antiplatelet therapy. For example, aspirin, the most widely used antiplatelet agent, inhibit the biosynthesis of thromboxane A 2 , the endogenous agonist that activates thromboxane receptors. The ADP antagonists such as clopidogrel and ticlopidine inhibit ADP‐mediated activation of purinergic P2Y 12 receptors. Glycoprotein IIb/IIIa antagonists such as abciximab, eptifibatide, and tirofiban inhibit GP IIb/IIIa receptors, which involve the final common pathway of platelet aggregation. Phosphodiesterase inhibitors are less widely used antiplatelet agents that potentiate intracellular cyclic AMP levels. Promising newer antiplatelet agents such as thrombin receptor antagonists with reduced bleeding liability, third‐generation thienopyridine ADP antagonists with improved potency and reversible ADP antagonists are at advanced stage of development.

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“…Eisai Co. has reported a PAR-1 antagonist based on the bicyclic amidine motif to be in clinical trials for acute coronary syndrome (Table ) . The structure of this compound is not known with certainty but is believed to be 28 (Figure ) on the basis of available information. , In the radioligand binding assay, this compound showed an IC 50 of 19 nM. It inhibited TRAP-induced human and guinea pig platelet-rich plasma (PRP) aggregations with IC 50 values of 31 and 97 nM, respectively.…”

Section: Non-peptide Thrombin Receptor Antagonistsmentioning

confidence: 99%

Thrombin Receptor (Protease Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects

Chackalamannil¹

2006

J. Med. Chem.

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3P-0836 Biological characterization of ER129614-06, a novel, non-peptide protease-activated receptor-1 (PAR-1) antagonist

Cited by 5 publications

References 0 publications

Molecular mechanisms regulating Proteinase‐Activated Receptors (PARs)

Molecular mechanisms regulating Proteinase‐Activated Receptors (PARs)

Antiplatelet Agents

Thrombin Receptor (Protease Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects

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