The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs

Kogushi, Motoji; Matsuoka, Toshifumi; Kawata, Tsutomu; Kuramochi, Hiroko; Kawaguchi, Shinki; Murakami, Kimiyo; Hiyoshi, Hironobu; Suzuki, Shinichi; Kawahara, Tetsuya; Kajiwara, Atsushi; Hishinuma, Ieharu

doi:10.1016/j.ejphar.2011.01.058

Cited by 41 publications

(32 citation statements)

References 29 publications

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“…In a guinea pig thrombosis model, oral administration of atopaxar prolonged the time to arterial occlusion compared with controls without prolonging bleeding time [28]. Also, atopaxar showed potent and selective inhibitory effects on platelet aggregation induced by thrombin and TRAP but had no effect on platelet aggregation induced by either ADP or collagen.…”

Section: Atopaxar (E5555)mentioning

confidence: 95%

Promises of PAR-1 Inhibition in Acute Coronary Syndrome

2011

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Platelet activation is a key process in the pathogenesis of acute coronary syndromes (ACS). Of the many triggers involved in this process, three are presumed to be critical: thromboxane A(2) (TBXA(2)) via the TBXA(2) receptor, adenosine diphosphate via the P2Y(12) receptor, and thrombin via the protease-activated receptor (PAR)-1. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y(12) inhibitors, the incidence of recurrent ischemic events remains high after ACS. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preclinical data and phase 2 clinical trials in patients with stable and unstable coronary disease support the potential of these compounds to improve clinical outcome. In this review we discuss the rationale for developing this novel class of agents with a focus on the two compounds in most advanced clinical development, vorapaxar (SCH 530348) and atopaxar (E5555).

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Section: Atopaxar (E5555)mentioning

confidence: 95%

Promises of PAR-1 Inhibition in Acute Coronary Syndrome

2011

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“…Their biological activities, such as anti-proliferative, thrombin receptor inhibitor, NMDA receptor antagonists, have attracted the attention of many research groups [79][80][81][82]. The existing methods are limited due to the problems associated with them.…”

Section: Synthesis Of Indolinesmentioning

confidence: 99%

Transition metal-free one-pot synthesis of nitrogen-containing heterocycles

et al. 2015

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One-pot heterocyclic synthesis is an exciting research area as it can open routes for the development of otherwise complex transformations in organic synthesis. Heterocyclic compounds show wide spectrum of applications in medicinal chemistry, chemical biology, and materials science. These heterocycles can be generated very efficiently through highly economical and viable routes using one-pot synthesis. In particular, the metal-free one-pot synthetic protocols are highly fascinating due to several advantages for the industrial production of heterocyclic frameworks. This comprehensive review is devoted to the transition metal-free one-pot synthesis of nitrogen-containing heterocycles from the period 2010-2013.

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“…Atopaxar inhibited binding of a tritiated synthetic agonist peptide, [ 3 H]SFLLRN, to PAR1 and inhibited human platelet aggregation in response to thrombin and a PAR1-specific agonist peptide ( Table 2) (27). In vivo, atopaxar demonstrated antithrombotic activity in several small animal models of thrombosis, including photochemically induced thrombosis in guinea pigs (27).…”

Section: Par1 Small-molecule Antagonistsmentioning

confidence: 99%

“…(a) Small molecules that target PAR1 have distinct structures. Vorapaxar is an analogue of the naturally occurring himbacine (31), atopaxar is a bicyclic amidine derivative (27), and ML161 parmodulin contains a 1,3-diaminobenzene core structure (51). (b) The PAR2 small-molecule antagonist GB88 is an N-terminal isoxazole, L-cyclohexylalanine, and L-isoleucine, but with a bulky C-terminal spiroindenepiperidine that confers PAR2 antagonism at low micromolar concentrations (59).…”

Section: Figurementioning

confidence: 99%

Challenges and Opportunities in Protease-Activated Receptor Drug Development

Hamilton

Trejo

2017

Annu. Rev. Pharmacol. Toxicol.

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Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable targets, the development of agents that target PARs specifically has been challenging. As a consequence, researchers have taken a remarkable diversity of approaches to develop pharmacological entities that modulate PAR function. Here, we present an overview of the diversity of therapeutic agents that have been developed against PARs. We further discuss PAR biased signaling and the influence of receptor compartmentalization, posttranslational modifications, and dimerization, which are important considerations for drug development.

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The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs

Cited by 41 publications

References 29 publications

Promises of PAR-1 Inhibition in Acute Coronary Syndrome

Promises of PAR-1 Inhibition in Acute Coronary Syndrome

Transition metal-free one-pot synthesis of nitrogen-containing heterocycles

Challenges and Opportunities in Protease-Activated Receptor Drug Development

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