3. Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist

Mederski, Werner W. K. R.; Dorsch, Dieter; Osswald, M.; Anzali, Soheila; Christadler, Maria; Schelling, Pierre; Wilm, Claudia; Fluck, Markus

doi:10.1016/s0960-894x(98)00301-1

Cited by 14 publications

(9 citation statements)

References 11 publications

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“…On a different day, the ETA receptor antagonist EMD-122946 (a gift from Prof. Schelling, Merck Darmstadt, Darmstadt, Germany) was administered to 10 normal and 8 MI swine at 3 mg/kg iv (18), and the exercise protocol was repeated. EMD-122946 has a pA 2 of 9.5 for ETA receptors and a pA2 of 6.0 for ETB receptors, indicating a 3,200-fold selectivity for ETA compared with ETB receptors (15). The dose of EMD-122946 administered in the present study does not block ET B receptors, inasmuch as we previously found that ET plasma concentrations are not influenced by this dose of EMD-122946, whereas tezosentan at the dose used in this study does increase plasma ET levels, indicating that the ET B receptor, which is responsible for ET clearance, is blocked by tezosentan, but not by EMD-122946 (18).…”

Section: Exercise Protocolsmentioning

confidence: 99%

Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction

Merkus

Houweling

Meiracker

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Left ventricular dysfunction in swine with a recent myocardial infarction (MI) is associated with neurohumoral activation, including increased catecholamines and endothelin (ET). Although the increase in ET may serve to maintain blood pressure and, hence, perfusion of essential organs such as the heart and brain, it could also compromise myocardial perfusion by evoking coronary vasoconstriction. In the present study, we tested the hypothesis that endogenous ET contributes to perturbations in myocardial O2 balance during exercise in remodeled myocardium of swine with a recent MI. For this purpose, 26 chronically instrumented swine (10 with and 16 without MI) were studied at rest and while running on a treadmill at 1-4 km/h. After MI, plasma ET increased from 3.2 +/- 0.4 to 4.9 +/- 0.3 pM (P < 0.05). In normal swine, blockade of ETA (by EMD-122946) or ETA-ETB (by tezosentan) receptors resulted in an increase in coronary venous PO2, i.e., coronary vasodilation at rest, which decreased during exercise. In contrast, neither ETA nor ETA-ETB receptor blockade resulted in coronary vasodilation in swine with MI. Coronary vasoconstriction to intravenous ET-1 infusion in awake resting swine was blunted after MI. To investigate whether factors released by cardiac myocytes contributed to decreased vascular responsiveness to ET, we performed ET-1 dose-response curves in isolated coronary arterioles (70-200 microm). Vasoconstriction to ET-1 in isolated arterioles from MI swine was enhanced. In conclusion, the vasoconstrictor influence of endogenous as well as exogenous ET on coronary circulation in vivo is reduced. Because the response of isolated coronary arterioles to ET is increased after MI, the reduced vasoconstrictor influence in vivo suggests modulation of ET receptor sensitivity by cardiac myocytes, which may serve to maintain adequate myocardial perfusion.

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Section: Exercise Protocolsmentioning

confidence: 99%

Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction

Merkus

Houweling

Meiracker

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Effects of ET A receptor blockade Swine ( n = 9 normal and n = 8 MI) received the ET A receptor antagonist EMD 122946 (a gift from Professor Schelling, E. Merck Darmstadt, Darmstadt, Germany) at a dose of 3 mg kg −1 intravenously, 90 min after they underwent the exercise protocol under control conditions (Merkus et al 2003). EMD 122946 has a pA 2 of 9.5 for ET A and a pA 2 of 6.0 for ET B receptors, indicating a 3200‐fold selectivity for ET A compared to ET B receptors (Mederski et al 1998). EMD 122946 in a dose of 3 mg kg −1 blocks the pressor response to intravenously infused ET.…”

mentioning

confidence: 99%

Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction

Houweling¹,

Merkus²,

Sorop³

et al. 2006

The Journal of Physiology

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We previously observed that pulmonary hypertension secondary to myocardial infarction (MI) in swine is characterized by elevated plasma endothelin (ET) levels and pulmonary vascular resistance (PVR). Consequently, we tested the hypothesis that an increased ET-mediated vasoconstrictor influence contributes to secondary pulmonary hypertension after MI and investigated the involvement of ET A and ET B receptor subtypes. Chronically instrumented swine with (MI swine; n = 25) or without (normal swine; n = 19) MI were studied at rest and during treadmill exercise (up to 4 km h -1 ), in the absence and presence of the ET A antagonist EMD 122946 or the mixed ET A /ET B antagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ET A blockade had no effect on PVR at rest or during exercise. Conversely, ET A /ET B blockade decreased PVR but only during exercise (at 4 km h -1 , from 3.0 ± 0.1 to 2.3 ± 0.1 mmHg min l -1 ; P ≤ 0.05). MI increased pulmonary arterial pressure and PVR both at rest and during exercise (both P ≤ 0.05). The increased pulmonary arterial pressure correlated with the increased plasma ET levels in resting MI swine (r = 0.71; P ≤ 0.01). Furthermore, the pulmonary vasoconstrictor response to ET-1 infusion was enhanced after MI (P ≤ 0.05). ET A /ET B blockade decreased PVR in MI swine from 3.6 ± 0.3 to 3.1 ± 0.5 mmHg min l -1 at rest and from 3.4 ± 0.3 to 2.4 ± 0.2 mmHg min l -1 during exercise at 4 km h -1 (both P ≤ 0.05). This increased response to mixed ET A /ET B blockade in MI compared to normal swine appeared to be the result of an increased ET A -mediated vasoconstriction, as ET A blockade decreased PVR in MI swine from 3.4 ± 0.4 to 2.8 ± 0.2 mmHg min l -1 at rest and from 3.1 ± 0.3 to 2.6 ± 0.2 mmHg min l -1 at 4 km h -1 (both P ≤ 0.05). In conclusion, increased plasma ET levels together with increased pulmonary resistance vessel responsiveness to ET result in an exaggerated pulmonary vasoconstrictor influence of ET in swine with a recent MI. This vasoconstrictor influence is the result of an emergent tonic ET A -mediated vasoconstriction in addition to the exercise-induced ET B -mediated vasoconstriction that is already present in normal swine. Congestive heart failure is the only major cardiovascular disorder of which the incidence has increased over the past decade, and this is principally due to a reduction in mortality associated with acute myocardial infarction (MI) (Colucci & Braunwald, 2001). The loss of viable myocardial tissue after MI causes left ventricular dysfunction leading to an increase in left ventricular filling pressure and neurohumoral activation particularly during exercise (Colucci & Braunwald, 2001;Haitsma et al. 2001;van der Velden et al. 2004;Merkus et al. 2005). The increase in left ventricular filling pressure is transmitted backwards into the pulmonary circulation, resulting in pulmonary congestion and an increase in pulmonary arterial blood pressure, thereby elevating right ventricular afterload (van Kats et al. 2000;Haitsma et al. 2001). The res...

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“…BQ 610 has an IC 50 (nM) for ET A binding at 0.64 and for ET B binding at 24000, resulting in a ET B /ET A IC 50 ratio of 37500 (personal communication from Thukuba Research Institute, Banyu Pharmaceutical Co., Ltd). EMD 122946 (a benzothiadiazole derivative) was recently developed by Merck as a highly selective ET A blocker (31), with an IC 50 (nM) for ET A binding at 0.032 and for ET B binding at 160 (ET B /ET A IC 50 ratio 5000). After IV administration EMD 122946 has rapid onset of action and quick clearance within hours (31), and these characteristics are roughly comparable to those of BQ 610.…”

mentioning

confidence: 99%

“…EMD 122946 (a benzothiadiazole derivative) was recently developed by Merck as a highly selective ET A blocker (31), with an IC 50 (nM) for ET A binding at 0.032 and for ET B binding at 160 (ET B /ET A IC 50 ratio 5000). After IV administration EMD 122946 has rapid onset of action and quick clearance within hours (31), and these characteristics are roughly comparable to those of BQ 610. Our study revealed that a 2 mg/kg i.v.…”

mentioning

confidence: 99%

“…However, it is not clear why this equipotent dose had different effects in the GBS model, when BQ 610 (but not EMD 122946) elevated PAP and PVRI. The effects of these two agents on ET B2 (ET B constictor) receptors have not been described, although it is suspected that selective ET A antagonists such as these agents do not bind to ET B constictor receptors as they do not abolish the pressor response to ET-1 (31). Both agents are known to be active at the range of pH (7.3-7.7) that was noted in the piglets during the experiments.…”

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confidence: 99%

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Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

et al. 2002

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Endothelin-1 can cause pulmonary vasoconstriction via endothelin-A (ET A ) receptor activation. We hypothesized that ET A blockers (EMD 122946 and BQ 610) would reduce hypoxiainduced (HYP) but not group B streptococcal infusion (GBS)-induced pulmonary hypertension in a juvenile whole animal model. Pulmonary hypertension was created by exposing chronically instrumented piglets to HYP (n ϭ 12) or heat-killed GBS (n ϭ 11). ET A blockade was produced by increasing bolus doses of EMD122946 or BQ 610. Pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), left atrial pressure, central venous pressure, and cardiac output were continuously measured. Pulmonary and systemic vascular resistance indices (PVRI and SVRI) were calculated. HYP doubled PAP and PVRI. Both ET A blockers decreased PAP and PVRI in a dose-dependent manner in HYP, with high doses decreasing PVRI to baseline and reducing PAP by 50%. GBS also doubled both PAP and PVRI. EMD 122946 did not change PAP or PVRI in GBS, although BQ 610 markedly increased PVRI (Ͼ100% increase with 0.15 mg/kg) and showed a trend toward increasing PAP. Both models showed minimal (Ͻ25%) changes in SAP or SVRI.Neither ETA blocker changed baseline hemodynamics in the absence of HYP or GBS. PaO 2 did not change with GBS but decreased with BQ 610. ET A receptor blockade attenuated hypoxic, but not GBS induced pulmonary hypertension. BQ 610 worsened PVRI and oxygenation in the GBS model. Differences in response to ET A blockade in pulmonary hypertension may be seen depending on the etiology (hypoxia versus infectionassociated), and the specific ET A antagonist used. Persistent pulmonary hypertension of the newborn (PPHN) affects over 10,000 infants every year in the United States (1) and is associated with considerable morbidity and mortality. Prenatal hypoxia may predispose to PPHN (1). Disorders such as bronchopulmonary dysplasia are also associated with elevated pulmonary pressures and pulmonary vascular remodeling in infants (2). Endothelin-1 (ET-1) is a 21-amino acid polypeptide with strong vasoactive properties that vary depending on age (3), vascular bed, dosage (4), and species (5). ET-1 acts via two different receptors in the vascular bed, ET A and ET B . In the pulmonary artery, ET A receptors mediate vasoconstriction and are found on vascular smooth muscle cells, while ET B receptors that are mostly located on endothelial cells mediate vasodilation (6). There is substantial evidence that ET-1 is elevated in neonates, infants (7-9), and older children (10) with pulmonary hypertension, and is a marker of disease severity. Animal studies have also indicated that ET-1 may play a role in the pathogenesis of neonatal pulmonary hypertension due to hypoxia (11), meconium aspiration (12), and increased pulmonary blood flow (13). Therefore, there has been interest in endothelin receptor blockade as a possible therapy for pediatric pulmonary hypertension.Our previous studies have shown that selective ET A receptor antagonists attenuate acute hypoxic pulmonary hypertensio...

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3. Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist

Cited by 14 publications

References 11 publications

Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction

Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction

Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction

Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

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