Discovery of TBC11251, a Potent, Long Acting, Orally Active Endothelin Receptor-A Selective Antagonist

Wu, Chia-Chien; Chan, Ming Fai; Stavros, Fiona; Raju, B.; Okun, Ilya; Mong, Seymour; Keller, Karin M.; Brock, Tommy A.; Kogan, Timothy P.; Dixon, Richard A. F.

doi:10.1021/jm9700068

Cited by 121 publications

(56 citation statements)

References 5 publications

(23 reference statements)

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“…Bosentan (Ro 47-0203; 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,29-bipyrimidin-4-yl]-benzenesulfonamide) (Clozel et al, 1994) was synthesized by Medicinal Chemistry, AstraZeneca (Mölndal, Sweden). Sitaxentan (TBC11251; N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-[2-(6-methyl-2H-1,3-benzodioxol-5-yl)acetyl]thiophene-3-sulfonamide) (Wu et al, 1997) and ambrisentan (BSF208075; LU208075; (2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid) (Riechers et al, 1996) were obtained from Chemtronica AB (Stockholm, Sweden). THLE cell lines (1A2, 2C9, 2C19, 2D6, 3A4, and Null) were obtained from Nestec (Lausanne, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Multiple Compound-Related Adverse Properties Contribute to Liver Injury Caused by Endothelin Receptor Antagonists

Kenna

Stahl

Eakins

et al. 2014

J Pharmacol Exp Ther

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Section: Methodsmentioning

confidence: 99%

Multiple Compound-Related Adverse Properties Contribute to Liver Injury Caused by Endothelin Receptor Antagonists

Kenna

Stahl

Eakins

et al. 2014

J Pharmacol Exp Ther

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“…6 We previously found that short-term systemic administration of sitaxsentan caused a greater decrease in pulmonary versus systemic vascular tone in patients with moderate to severe HF, suggesting that ET plays a role in mediating pulmonary hypertension in such patients. 7 To directly test this hypothesis, sitaxsentan was infused into a segmental pulmonary artery, and the effect on pulmonary arterial tone was assessed by measuring the change in local blood flow velocity using a Doppler-tipped wire in patients with left ventricular (LV) systolic failure and control subjects with normal LV function.…”

mentioning

confidence: 90%

Endothelin Mediates Increased Pulmonary Vascular Tone in Patients With Heart Failure

2002

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Background-In patients with chronic heart failure (HF), the pulmonary circulation is a major source of endothelin-1 (ET), and ET levels correlate with pulmonary vascular resistance (PVR). The role of ET in causing pulmonary vasoconstriction in HF is not known, however, in part because of the confounding effects of ET receptor antagonists on systemic hemodynamics. Methods and Results-To directly test the hypothesis that ET causes pulmonary vasoconstriction in patients with HF, we infused the selective ET A receptor antagonist sitaxsentan at increasing rates (0.3125 to 10 mg/min) into a left lower-lobe segmental pulmonary artery in 8 patients with left ventricular (LV) systolic failure (LV ejection fraction, 24Ϯ4%) and 4 control subjects with normal LV function. Changes in local PVR distal to the infusion site were assessed by measuring the change in pulmonary blood flow velocity with a Doppler-tipped wire and the mean pulmonary artery pressure (MPAP). Total PVR at baseline was elevated in HF patients (177Ϯ23 dyne · s · cm Ϫ5 ) versus controls (89Ϯ21 dyne · s · cm Ϫ5; PϽ0.05). In patients with HF, sitaxsentan caused an infusion rate-dependent decrease in local PVR (PϽ0.05 versus baseline; PϽ0.05 versus controls). In contrast, sitaxsentan infusion had no effect on local PVR in controls. Heart rate, mean arterial pressure, cardiac index, and MPAP were not affected by sitaxsentan in either group. Key Words: endothelin Ⅲ heart failure Ⅲ hypertension, pulmonary S econdary reactive pulmonary hypertension is frequent in patients with left ventricular systolic failure. 1 In such patients, plasma endothelin-1 (ET) is elevated and correlates with survival. 2 The pulmonary circulation is a major source of ET in heart failure (HF), and pulmonary ET spillover correlates strongly with pulmonary vascular resistance (PVR), 3 leading to the suggestion that ET contributes to secondary pulmonary hypertension in patients with chronic HF. 1,4 In vitro, ET is a potent constrictor in pulmonary resistance vessels. Stimulation of ET A receptors uniformly causes constriction, whereas stimulation of ET B receptors may cause either constriction or dilation, the latter reflecting the release of nitric oxide. 5 The contribution of ET to secondary pulmonary hypertension in patients with HF is not known, in part because of the difficulty of assessing pulmonary vascular reactivity in the presence of confounding changes in systemic hemodynamics. Conclusion-SelectiveSitaxsentan is a nonpeptide, high-affinity competitive antagonist that is 6000-fold selective for the human ET A (versus ET B ) receptor. 6 We previously found that short-term systemic administration of sitaxsentan caused a greater decrease in pulmonary versus systemic vascular tone in patients with moderate to severe HF, suggesting that ET plays a role in mediating pulmonary hypertension in such patients. 7 To directly test this hypothesis, sitaxsentan was infused into a segmental pulmonary artery, and the effect on pulmonary arterial tone was assessed by measuring the change in local ...

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“…TBC-3214 (25 mg/kg body wt; Texas Biotechnology) was dissolved in drinking water, administered 3-5 days before surgery, and continued for the duration of the specific experimental group (i.e., 1 and 5 days or 8 wk postfistula). This dose of TBC-3214 was selected based on the manufacturer's (Texas Biotechnology) specified oral bioavailability concentrations documented in previous in vitro studies (42,53,54). Use of this class of ETA receptor antagonist in heart failure patients was capable of improving pulmonary hemodynamics but did not affect systemic vascular resistance (for review, see Ref.…”

Section: Animal Welfarementioning

confidence: 99%

ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

Murray¹,

McMillan²,

Brower³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Murray DB, McMillan R, Brower GL, Janicki JS. ETA selective receptor antagonism prevents ventricular remodeling in volume-overloaded rats. Am J Physiol Heart Circ Physiol 297: H109 -H116, 2009. First published May 8, 2009 doi:10.1152/ajpheart.00968.2008.-The objective of this study was to investigate the ability of selective endothelin receptor subtype A (ET A) endothelin receptor antagonism (ETA) to prevent the acute myocardial remodeling process secondary to volume overload. Left ventricular tissue from sham-operated (Sham) and untreated (Fist), and TBC-3214 (Fist ϩ ETA, 25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 )-treated fistula animals was analyzed for mast cell density, matrix metalloproteinase (MMP) activity, and extracellular collagen volume fraction (CVF) 1 and 5 days following the initiation of volume overload. Compared with Fist, ETA treatment prevented the increase in left ventricular mast cell density at 1 day and 5 days. Additionally, at 1 day postfistula, a substantial decrease in MMP-2 activity below Sham levels was observed following endothelin receptor antagonism (1.7 Ϯ 0.7 vs. 0.3 Ϯ 0.3 vs. 0.9 Ϯ 0.2 arbitrary activity units, Fist vs. Fist ϩ ETA vs. Sham, P Յ 0.05). This same effect was also seen at 5 days postfistula (1.9 Ϯ 0.3 vs. 0.5 Ϯ 0.1 arbitrary activity units, Fist vs. Fist ϩ ETA, P Յ 0.05). The marked decrease in myocardial CVF seen in Fist hearts (0.7 Ϯ 0.1 vs. 1.6 Ϯ 0.1% myocardial area, Fist vs. Sham, P Յ 0.05) was prevented by ETA (1.7 Ϯ 0.1% Fist ϩ ETA, P Ͻ 0.05 vs. Fist). This preservation of the collagen matrix was also present on day 5 in the TBC-treated group vs. the Fist group (1.0 Ϯ 0.1 vs. 1.4 Ϯ 0.1%, Fist vs. Fist ϩ ETA, P Յ 0.01). Furthermore, an 8-wk preventative treatment with ETA significantly attenuated the increase in left ventricular end systolic and diastolic volumes compared with untreated fistula hearts. In conclusion, the novel findings of this study indicate that the activation of cardiac mast cells and subsequent MMP activation/collagen degradation during the acute stages of volume overload are prevented by blockade of the ET A receptor subtype. Furthermore, by preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits.endothelin-1; mast cell; matrix metalloproteinase; TBC-3214 ENDOTHELIN (ET)-1 is a potent neurohormone produced throughout the cardiovascular system, and the observation that plasma ET-1 is elevated in patients with heart failure is suggestive of a role in the pathophysiology of heart failure (16,19,34,40,47). The cardiovascular effects of ET-1 (a 21-amino-acid peptide) are dictated by binding to one of two G protein-linked receptor subtypes [endothelin receptor subtypes A (ET A ) or B (ET B )] (23). In the heart and vasculature, binding and activation of ET A is known to mediate powerful vasoconstrictor and pressor affects, in addition to chronotropic and ionotropic effects (12,25). The ET B receptor subtype is responsible for systemic clearance of circulating ...

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Discovery of TBC11251, a Potent, Long Acting, Orally Active Endothelin Receptor-A Selective Antagonist

Cited by 121 publications

References 5 publications

Multiple Compound-Related Adverse Properties Contribute to Liver Injury Caused by Endothelin Receptor Antagonists

Multiple Compound-Related Adverse Properties Contribute to Liver Injury Caused by Endothelin Receptor Antagonists

Endothelin Mediates Increased Pulmonary Vascular Tone in Patients With Heart Failure

ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

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Discovery of TBC11251, a Potent, Long Acting, Orally Active Endothelin Receptor-A Selective Antagonist

Cited by 121 publications

References 5 publications

Multiple Compound-Related Adverse Properties Contribute to Liver Injury Caused by Endothelin Receptor Antagonists

Multiple Compound-Related Adverse Properties Contribute to Liver Injury Caused by Endothelin Receptor Antagonists

Endothelin Mediates Increased Pulmonary Vascular Tone in Patients With Heart Failure

ETAselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

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ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats