Novel benzo[1,4]diazepin-2-one derivatives as endothelin receptor antagonists

Since its discovery in 1988 by Yanagisawa et al., endothelin (ET), a potent vasoconstrictor, has been widely implicated in the pathophysiology of cardiovascular, cerebrovascular, and renal diseases. Many research groups have embarked on the discovery and development of ET receptor antagonists for the treatment of such diseases. While several compounds, e.g., ambrisentan 2, are in late clinical trials for various indications, one compound (bosentan, Tracleer) is being marketed to treat pulmonary arterial hypertension. Inspired by the structure of ambrisentan 2, we designed a novel class of ET receptor antagonists based on a 1,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-one scaffold. Here, we report on the preparation as well as the in vitro and in vivo structure-activity relationships of these derivatives. Potent dual ET(A)/ET(B) receptor antagonists with affinities in the low nanomolar range have been identified. In addition, several compounds efficiently reduced arterial blood pressure after oral administration to Dahl salt sensitive rats. In this animal model, the efficacy of the benzo[e][1,4]diazepin-2-one derivative rac-39au was superior to that of racemic ambrisentan, rac-2.     

Pathophysiological roles of endothelin receptors in cardiovascular diseases

Endothelin (ET)-1 derived from endothelial cells has a much more important role in cardiovascular system regulation than the ET-2 and ET-3 isoforms. Numerous lines of evidence indicate that ET-1 possesses a number of biological activities leading to cardiovascular diseases (CVD) including hypertension and atherosclerosis. Physiological and pathophysiological responses to ET-1 in various tissues are mediated by interactions with ET(A)- and ET(B)-receptor subtypes. Both subtypes on vascular smooth muscle cells mediate vasoconstriction, whereas the ET(B)-receptor subtype on endothelial cells contributes to vasodilatation and ET-1 clearance. Although selective ET(A)- or nonselective ET(A)/ET(B)-receptor antagonisms have been assumed as potential strategies for the treatment of several CVD based on clinical and animal experiments, it remains unclear which antagonisms are suitable for individuals with CVD because upregulation of the nitric oxide system via the ET(B) receptor is responsible for vasoprotective effects such as vasodilatation and anti-cell proliferation. In this review, we have summarized the current understanding regarding the role of ET receptors, especially the ET(B) receptor, in CVD.     

Nonpeptide endothelin antagonists in clinical development

Endothelins (ET-1, ET-2 and ET-3) are 21-amino-acid peptides with two disulfide bonds that belong to the sarafotoxin family. ET-1, ET-2 and ET-3 are produced endogenously from preproendothelin to give big endothelins, which are cleaved by endothelin-converting enzyme (ECE) to yield the active protein. Endothelin has been shown to play important physiological and pathological roles by interacting with its G-protein-coupled receptors. There are two cloned ET receptors: the ET(A) receptor, which is selective for ET-1, and the ET(B) receptor, which binds ET-1, ET-2 and ET-3 with similar affinities. Since the discovery of endothelin, and especially since the availability of peptide ET antagonists such as BQ-123 and BQ-788, and nonpeptide compounds such as bosentan, considerable effort has been spent on better understanding the role of endothelin and its receptor antagonists. As a result, endothelin has been implicated in a variety of serious diseases, such as congestive heart failure, hypertension, pulmonary hypertension and prostate cancer. Research in pharmaceutical and biotechnology laboratories has generated many endothelin antagonists with either sulfonamide or triaryl carboxylic acid scaffolds, and a number of ET(A)-selective or nonselective ET(A)/ET(B) endothelin antagonists have entered clinical trials. This article will review the small-molecule ET(A)-selective and nonselective ET(A)/ET(B) antagonists that are under clinical evaluation, and highlight a member of this group of compounds, sitaxsentan. A summary of the medicinal chemistry that led to the identification of sitaxsentan will be presented, followed by selected animal and human clinical trial data. (c) 2001 Prous Science. All rights reserved.     

The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET(A) receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.     

内皮素受体阻滞剂的合成研究进展

内皮素具有很强的缩血管作用,与受体结合可产生广泛的生物学效应,它参与了多种心脑血管疾病的发生和发展过程,研究其受体阻滞剂具有重要意义.现综述了不同结构内皮素受体阻滞剂合成研究的进展,供该类新药的合成研发参考.     

Role of endothelin in the pathogenesis of acute renal failure

Shortly after the discovery of endothelin (ET) in 1988, it was suggested that ET might be an important mediator of acute renal failure (ARF) because of its intense renal vasoconstrictive properties. Evidence has accumulated for supporting this hypothesis: Exogenous ET infused into the kidney is able to decrease renal blood flow and glomerular filtration rate to create conditions that can lead to ARF; ET also has glomerular and tubular effects; and ET mRNA expression, ET content and its affinity for ET receptors are elevated in ARF. In addition, since physiological and pathophysiological actions of ET in renal tissue are mediated by interaction with ET(A) and ET(B) receptor subtypes, a number of ET receptor antagonists have been developed and used to deter- mine the pathophysiological role of ET peptide and ET receptor subtypes in the kidney. Many reports confirm beneficial effects of selective ET(A) and nonselective ET(A)/ET(B) receptor antagonists on renal dysfunction and degeneration in ARF. A recent study shows that renal dysfunction and histological damage observed in ischemic ARF are not improved by the treatment with a selective ET(B) receptor antagonist. Although the pathophysiological role of ET(B)-mediated ET action in the development of ARF is not fully understood, these observations strongly suggest that up-regulated endogenous ET contributes to the pathogenesis of ARF exclusively via ET(A) receptors and that compounds with ET(A) receptor antagonism are useful for the treatment of ARF. It is expected that such agents will have clinical applications in the future, and a number of drug candidates are now in development.     

The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system

Clinical trials have established bosentan, an orally active non-selective endothelin (ET) receptor antagonist, as a beneficial treatment in pulmonary hypertension. Trials have also shown short-term benefits of bosentan in systemic hypertension and congestive heart failure. However, bosentan also increased plasma levels of ET-1, probably by inhibiting the clearance of ET-1 by endothelin type B (ET(B)) receptors, and this may mean its effectiveness is reduced with long-term clinical use. Preliminary data suggests that selective endothelin type A (ET(A)) receptor antagonists (BQ-123, sitaxsentan) may be more beneficial than the non-selective ET receptor antagonists in heart failure, especially when the failure is associated with pulmonary hypertension. Experimental evidence in animal disease models suggests that non-selective ET or selective ET(A) receptor antagonism may have a role in the treatment of atherosclerosis, restenosis, myocarditis, shock and portal hypertension. In animal models of myocardial infarction and/or reperfusion injury, non-selective ET or selective ET(A) receptor antagonists have beneficial or detrimental effects depending on the conditions and agents used. Thus clinical trials of the non-selective ET or selective ET(A) receptor antagonists in these conditions are not presently warranted. Several selective endothelin-converting enzyme inhibitors have been synthesised recently, and these are only beginning to be tested in animal models of cardiovascular disease, and thus the clinical potential of these inhibitors is still to be defined.     

Real-time nanoscale proteomic analysis of the novel multi-kinase pathway inhibitor rigosertib to measure the response to treatment of cancer

Endothelin (ET) is a powerful vasoconstrictor that affects vascular tone and blood pressure; however, recent evidence suggests that ET acts as an autocrine or paracrine factor and plays a role in the pathogenesis of atherosclerosis. In humans and in animal models, elevated plasma ET concentrations are associated with hypercholesterolaemia and atherosclerosis. ET and its receptors are located in endothelial cells, macrophages and smooth muscle cells of atherosclerotic and arteriosclerotic lesions. In vitro, endothelial cells, macrophages and smooth muscle cells synthesise ET and express ET receptors. Oxidised low density lipoprotein (LDL), growth factors, vasoactive peptides, and cytokines induce ET gene expression and protein synthesis. Conversely ET stimulates the synthesis of growth factors, inflammatory mediators, chemokines and adhesion molecules. In animal models, ET receptor antagonists decrease fatty streak progression during hypercholesterolaemia, and inhibit the formation of a fibrous neointima following arterial balloon catheter injury. It appears likely that ET indirectly promotes several phases of atherogenesis such as monocyte diapedesis into the artery wall, and the migration and proliferation of vascular smooth muscle cells. In summary, ET appears to be intricately involved in the elaboration of paracrine and autocrine factors mediating inflammation and wound healing. Pharmacological blockade of ET receptors inhibits the development of vascular lesions as a result of either hypercholesterolaemia or physical injury. Thus, it is possible that ET receptor antagonists could be used therapeutically to treat human vascular diseases such as atherosclerosis.     

New expansion of endothelin research: perspectives for clinical application of endothelin-receptor antagonists

Three isopeptides of endothelin (ET-1, -2, and -3) exert various actions through stimulation of two sub-types of receptor (ETA and ETB). Vascular endothelial cells produce only ET-1. In addition to its powerful vasoconstrictor action, ET-1 has direct mitogenic actions on cardiovascular tissues, as well as comitogennic actions with a wide variety of growth factors and vasoactive substances. ET-1 also promotes the synthesis and secretion of growth factors and various substances, including extracellular constituents. These effects of endogenous ET-1 would naturally be thought to be concerned with the development and/or aggravation of chronic cardiovascular diseases; e.g., hypertension, pulmonary hypertension, vascular remodeling (stenosis, atherosclerosis), renal failure, and heart failure. A large number of peptide and orally active non-peptide endothelin receptor antagonists have been developed, and utilized to analyze physiological and pathophysiological roles of endogenous ET-1. These antagonists have been shown to exert excellent therapeutic effects in animal models of various kinds of diseases by either acute or chronic treatment. Therapeutic treatment of patients suffering from the above-mentioned cardiovascular diseases with ET-receptor antagonists have also been taking place, and bosentan (ETA/ETB antagonist) was recently approved by the FDA as a formal therapeutic drug for pulmonary hypertension. In this review, perspectives for therapeutic applicability of ET-receptor antagonists will be explored.     

Binding of a new bioactive 31-amino-acid endothelin-1 to an endothelin ET(B) or ET(B)-like receptor in porcine lungs

Endothelin-1-(1-31) is a new bioactive 31-amino-acid-length peptide generated from big endothelin-1 by chymase or other chymotrypsin-type proteases with various pathophysiologic functions. In this study, we have detected the specific and monophasic binding of [125I]endothelin-1-(1-31) in porcine lung membranes. Competition studies of [125I]endothelin-1-(1-31) binding by unlabeled endothelin-1-(1-31), endothelin-1, endothelin-3, and antagonists and agonists of endothelin ET(A) and ET(B) receptors suggest that the binding protein is an endothelin ET(B) or ET(B)-like receptor rather than an endothelin ET(A) receptor in porcine lungs. Kinetic studies showed that the affinity of endothelin-1-(1-31) to its receptor was approximately one order of magnitude lower than that of endothelin-1, and that the specific binding of endothelin-1-(1-31) was about 19% of endothelin-1 binding. The binding of [125I]endothelin-1-(1-31) was extremely slow, slower even than that of endothelin-1, and nearly irreversible. This unique quasi-irreversibility may explain the slow-onset and long-lasting biologic effects of this peptide in vivo.     

SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction ENDOTHELIN RECEPTORS IN NORMAL AND DISEASED KIDNEYS

1. Endothelin-1 (ET-1), the most potent vasoconstrictor yet identified, mediates a multitude of responses in various tissues including the kidney. The biological responses of ET-1 are mediated by specific cell surface receptors classified as ET_A and ET_B. Species differences are observed in the distribution as well as function of these ET receptors.
2. Involvement of ET has been demonstrated in a number of renal diseases, including ischaemia-induced acute renal failure, chronic renal failure, radiocontrast and cyclosporin-induced nephrotoxicity. ET antibodies as well as ET receptor antagonists have been shown to be beneficial in these disease models.     

The role of endothelin receptor antagonists in cardiovascular pharmacotherapy

Endothelin (ET) is a hormone produced predominantly by endothelial cells which has been recognised to play a significant role in the development of several cardiovascular disease states. In order to combat the deleterious effects of ET, several ET-receptor antagonists (ETRA) are currently in clinical development. The agents developed thus far inhibit the actions of ET through either selective inhibition of the ET(A) receptors or non-selective inhibition of both ET(A) and ET(B) receptors. However, due to the differing proportions of the two receptor subtypes in various tissues, animal models and pathologies, it remains a matter of debate whether receptor selective agents impart significant clinical benefits over non-selective agents. This paper seeks to briefly summarise the important preclinical and clinical effects that have been reported in the literature and will attempt to provide a rationale for the use of both types of ETRAs in the treatment of both systemic and pulmonary hypertension as well as chronic heart failure (CHF).     

Overview Central & Peripheral Nervous Systems: Anti-epileptic agents: recent developments

Intensive research, stemming from experimental and clinical findings, has been carried out in the last few years into a possible role for endothelin (ET) in the mediation of acute and chronic renal dysfunction. So far, a number of pre-clinical studies have been performed with ET antagonists. These were aimed at exploring the possibility that modulation of ET synthesis or activity at the receptor level could ameliorate the renal haemodynamic and/or structural damage associated with various nephropathies. This review will cover patenting activity concerning endothelin-converting enzyme (ECE) inhibitors, either presently in pre-clinical development or that have appeared recently in patent literature. Special emphasis will be placed on the more significant developments and patent applications concerning selective and unselective ET receptor antagonists, and the few compounds for which in vivo pre-clinical data are already available will be identified and separated from those that have only been tested in vitro.     

Selective and mixed endothelin receptor antagonism in cardiovascular disease

Within five years of discovering endothelin (ET-1) in 1988, the first report of an orally available ET receptor antagonist was published. Within twelve years, bosentan, the first ET receptor antagonist to gain marketing authorization, was made available for the treatment of pulmonary artery hypertension (PAH). Since this milestone in ET biology, several ET receptor antagonists have been developed, principally to target cardiovascular disease states. ET-1 acts through two receptors--ET(A) and ET(B). Currently, the mixed antagonist, bosentan, and the selective ET(A) antagonist, sitaxsentan, are both licensed for the treatment of PAH, and clinical trials with these and other agents are ongoing for many diseases, including scleroderma, diabetic nephropathy and prostate cancer. Although there has been no argument about the importance of blocking ET(A) receptors, there remains a long-running debate as to whether additional ET(B) antagonism is of benefit, and this is the topic of the following review.     

Regulations of astrocytic functions by endothelins: roles in the pathophysiological responses of damaged brains

The receptors for endothelins (ETs) are classified into the ET(A) and ET(B) types. ET(B) receptors are highly expressed in astrocytes, but pharmacological usages of this receptor are not clarified. In this article, recent studies on the pathophysiological roles of astrocytic ET(B) receptors in the brain are reviewed. The administration of ET(B) agonists and antagonists in nerve injury models showed that several astrocytic functions are regulated by ET(B) receptors. The activation of ET(B) receptors causes morphological alterations and proliferation of cultured astrocytes. Astrocytes produce various bio-active substances that can affect damage to nerve tissues. ETs stimulate the production of neurotrophic factors by astrocytes. This action improves impaired brain functions. On the other hand, the production of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF), which induce brain edema, also are stimulated by ETs. These findings indicate that astrocytic functions are effectively regulated by modulations of ET(B) receptors. In brain insults and neurodegenerative diseases, these functions of astrocytes affect the protection and repair of damaged nerve tissues. Thus, astrocytic ET(B) receptors could be a target for novel types of neuroprotective drugs.     

The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system

Clinical trials have established bosentan, an orally active non-selective endothelin (ET) receptor antagonist, as a beneficial treatment in pulmonary hypertension. Trials have also shown short-term benefits of bosentan in systemic hypertension and congestive heart failure. However, bosentan also increased plasma levels of ET-1, probably by inhibiting the clearance of ET-1 by endothelin type B (ET_B) receptors, and this may mean its effectiveness is reduced with long-term clinical use. Preliminary data suggests that selective endothelin type A (ET_A) receptor antagonists (BQ-123, sitaxsentan) may be more beneficial than the non-selective ET receptor antagonists in heart failure, especially when the failure is associated with pulmonary hypertension. Experimental evidence in animal disease models suggests that non-selective ET or selective ET_A receptor antagonism may have a role in the treatment of atherosclerosis, restenosis, myocarditis, shock and portal hypertension. In animal models of myocardial infarction and/or reperfusion injury, non-selective ET or selective ET_A receptor antagonists have beneficial or detrimental effects depending on the conditions and agents used. Thus clinical trials of the non-selective ET or selective ET_A receptor antagonists in these conditions are not presently warranted. Several selective endothelin-converting enzyme inhibitors have been synthesised recently, and these are only beginning to be tested in animal models of cardiovascular disease, and thus the clinical potential of these inhibitors is still to be defined.     

The therapeutic potential of PD156707 and related butenolide endothelin antagonists

Plasma concentrations of the peptide endothelin (ET) are elevated in several cardiovascular diseases. Animal studies suggest that activation of ET receptors may contribute to the increase in vascular resistance and remodelling of cardiovascular tissues that are characteristic of these pathologies. Antagonists of these receptors may therefore have important clinical potential. PD156707 (Parke-Davis) is one of a series of novel, orally-active butenolide endothelin antagonists and is highly selective for the ETA receptor. In man, this subtype mediates the profound vasoconstrictor effects of the ET peptides, and blockade of the ETA receptor may therefore produce beneficial vasodilatation. The advantage of selective ETA receptor antagonism is that it leaves unaffected vascular ETB receptors, which mediate vasorelaxation, and non-vascular ETB receptors, particularly in the lung and kidneys, which act to clear ET from the plasma. PD156707 exhibits subnanomolar affinity and greater than 1000-fold selectivity for human ETA receptors and potently inhibits ET-1-mediated vasoconstriction in human isolated blood vessels. In rats, PD156707 has good oral bioavailability (41%) and a relatively short terminal t1/2 of approximately 1 h. Structural analogues of PD156707 that have comparable selectivity and potency for the ETA receptor are reported to have even better oral bioavailability and longer plasma t1/2 values. Preclinical studies with PD156707 indicate efficacy in animal models of congestive heart failure (CHF), pulmonary hypertension (PH) and cerebral ischaemia. We await data from clinical trials to confirm the therapeutic potential of the ETA-selective butenolide antagonists in man.     

Endothelin receptor antagonists: a new therapeutic option for improving the outcome after solid organ transplantation?

Initially described as the most potent vasoconstrictor peptide, endothelin (ET) has also been shown to possess extraordinary immunomodulatory and proinflammatory properties. Because of this broad spectrum of biological activities, a possible role of the ET-system in solid organ transplantation has soon become a focus of research. Several studies demonstrated a pathogenetic involvement of ET in ischemia/reperfusion injury of heart, liver, kidney, and lung grafts. ET accumulates during cold storage of organs and can be detected in the effluent preservation solution. In addition ET is very, likely to play a pivotal role in the development of chronic rejection, which represents the major cause of late allograft loss. Increased expression of components of the ET-system has been described in areas of neointimal proliferation, a hallmark of chronic graft rejection. Both selective ET-A as well as non-selective ET-A/B receptor antagonists improved histomorphological and functional sequelae of chronic rejection. However these data have largely been derived from experimental animal transplantation, and ET receptor blockers have only recently been introduced in clinical medicine. A significant number of investigational drugs are now being tested in humans, with a main focus on cardiovascular diseases, such as congestive heart failure and pulmonary hypertension. First results have markedly dampened the initial enthusiastic vision of ET receptor blockers being organoprotective super-weapons. Thus the clinical potential of ET antagonists in general, and especially in solid-organ transplantation, is still to be defined.