Superiority of YM598 over atrasentan as a selective endothelin ETA receptor antagonist

Yuyama, Hironori; Noguchi, Yukiko; Fujimori, A.; Ukai, Masashi; Fujiyasu, Noriko; Ohtake, Akiyoshi; Sato, Shuichi; Sudoh, Katsumi; Sasamata, Masao; Miyata, Keiji

doi:10.1016/j.ejphar.2004.07.003

Cited by 12 publications

(4 citation statements)

References 18 publications

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“…Bosentan, a tetra-substituted pyrimidine (15), has only slightly higher affinity for ET A -than ET B -receptors and is considered a non-selective dual ET A/B receptor antagonist. The estimate of its affinity for the receptors varied with the preparations used but was approximately one logarithmic step in favor of ET A receptors (15,53,94). The therapeutic efficacy of bosentan has been proven in several double-blind and placebo-controlled studies in patients with PAH (48,64).…”

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confidence: 99%

Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Vatter

Seifert

2006

Cardiovascular Drug Reviews

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Increasing numbers of experimental investigations and recently also of clinical trials strongly suggest an integral involvement of the endothelin (ET)-system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system. Ambrisentan (LU 208075), a selective ET A -receptor antagonist, is an orally active diphenyl propionic acid derivative. It has been shown to have a very promising efficacy to safety ratio in the initial clinical trials. Phase II and Phase III trials with ambrisentan in pulmonary arterial hypertension have been performed. The pharmacological properties and data from the experimental investigations suggest additional possible uses of ambrisentan in the prevention of reperfusion injury after organ transplantation and in restenosis following coronary artery dilatation. Furthermore, the pharmacological profile of ambrisentan indicates that this drug may also be suitable in the treatment of cerebrovascular disorders. In the present article basic investigations, animal studies and clinical trials with ambrisentan are reviewed. This review may help to define pathophysiological conditions, in which ambrisentan could be indicated and further evaluated in appropriate preclinical and clinical trials.

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confidence: 99%

Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Vatter

Seifert

2006

Cardiovascular Drug Reviews

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“…In the presence of ET1, the plateau phase was sustained up to an experimental period of 1 h. ETA blocker (BQ-123, 1 µ M ) and ETB blocker (BQ-788, 1 µ M ) were used to determine the receptor(s) responsible for mediating ET1-induced tonic contraction in the rabbit IVC [7, 22, 23]. Due to the reported superior selectivity of BQ-788 for ETB blockade [23, 24], BQ-788 was applied first to IVC precontracted with ET1. As shown in figure 1, ETB blockade with BQ-788 resulted in an 8.0 ± 3.0% inhibition (n = 6 rings from 4 rabbits, p = 0.0300, Student’s paired t test) in ET1-induced tonic contraction.…”

Section: Resultsmentioning

confidence: 99%

Endothelin-1-Mediated Wave-Like [Ca<sup>2+</sup>]<sub>i</sub> Oscillations in Intact Rabbit Inferior Vena Cava

Dai

Lee²,

Poburko³

et al. 2007

J Vasc Res

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Endothelin-1 (ET1) is an endogenous vasoconstrictor released by the vascular system to regulate the contractility of vascular smooth muscle cells (VSMC). It is implicated in the pathogenesis of hypertension and diabetic vasculopathy. In rabbit inferior vena cava (IVC), 10 nM ET1 induces tonic contraction mainly via type A endothelin receptor activation. Using confocal imaging of Fluo-3 loaded in thein situ VSMC within the intact IVC, we found that ET1 elicited [Ca²⁺]_i oscillations with an average frequency of 0.31 ± 0.01 Hz. These [Ca²⁺]_i oscillations occurred as repetitive Ca²⁺ waves traveling along the longitudinal axis of the cells with an average velocity of 29 ± 3 µm/s. The Ca²⁺ waves were not synchronized between neighboring VSMC nor were they propagated between them. Nifedipine (10 µM) inhibited the tonic contraction by 27.0 ± 5.0% while SKF96365 (50 µM) abolished the remaining contraction. In a parallel Ca²⁺ study, nifedipine reduced the frequency of the oscillations to 0.22 ± 0.01 Hz while SKF96365 abolished the remaining [Ca²⁺]_i oscillations. Subsequent application of 25 mM caffeine elicited no further Ca²⁺ signal. Thus, we conclude that ET1 stimulates tonic contraction in the rabbit IVC by inducing [Ca²⁺]_i oscillations and that stimulated Ca²⁺ entry through both the L-type voltage-gated Ca²⁺ channels and a nifedipine-resistant and SKF96365-sensitive pathway is crucial for the maintenance of [Ca²⁺]_i oscillations and tonic contraction.

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“…Unfortunately, these biochemical effects did not translate to clinical benefit as there were no significant differences in bone scan index between the 10 mg dose and placebo groups, although it should be mentioned that bone scans were not available for most of the patients, which might have skewed the results. The role of atrasentan or newer endothelin inhibitor YM598 [178] in prostate cancer is to be investigated further.…”

Section: Endothelinmentioning

confidence: 99%

Targeted therapies for prostate cancer

Asatiani

Gelmann²

2005

Expert Opinion on Therapeutic Targets

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The development of targeted therapies for prostate cancer has exploited various elements of prostate biology. The androgen-dependence of prostate cancer continues to be the focus for the development of new drugs and the analysis of details of the intermolecular interactions of the androgen receptor. Importantly, new applications of androgen ablation therapy have proven to have the greatest effect on cause-specific and overall survival during the last decade. Prostate epithelial cells express a number of tissue-specific proteins that have been the target either for antibody-directed therapies, in the case of prostate-specific membrane antigen, or target-activated therapies in the case of prostate-specific antigen, a serine protease. Prostate-specific proteins have also been targeted by the development of vaccines that have entered clinical trials. Humanized monoclonal antibodies and small molecules designed to inhibit oncogenic signalling pathways have been subjected to clinical trials in prostate cancer with limited success. The application of pathway inhibitors to prostate cancer therapy has been limited because no common dominant oncogenic mutation affecting signal kinase activation in prostate cancer has yet been identified. The interaction of signal kinase inhibitors with androgen ablation and with cytotoxic chemotherapy remains to be explored.

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Superiority of YM598 over atrasentan as a selective endothelin ETA receptor antagonist

Cited by 12 publications

References 18 publications

Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Endothelin-1-Mediated Wave-Like [Ca<sup>2+</sup>]<sub>i</sub> Oscillations in Intact Rabbit Inferior Vena Cava

Targeted therapies for prostate cancer

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