• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • In summary A is a


    In summary, A-216546 is a potent, orally available endothelin receptor antagonist with a high selectivity for the endothelin ETA receptor. The potency and bioavailability of A-216546 suggest that it will have important utility for preclinical evaluation of the pathophysiology of the endothelin system. In particular, the >25,000-fold selectivity towards the endothelin ETA receptor makes A-216546 a useful tool in studying the pathophysiological role of endothelin ETA receptor in an unequivocal manner. Furthermore, A-216546 is being considered for clinical development as a therapeutic agent for chronic treatment of human diseases involving endothelin-1 mediated by the endothelin ETA receptor. The high selectivity of A-216546 for the endothelin ETA receptor may provide a potential advantage in that a higher dose may be used under chronic dosing conditions to achieve a greater tissue penetration, resulting in a greater local and selective antagonism of the endothelin ETA receptor without a concern over blocking the endothelin ETB receptor.
    Introduction Surgery remains the most reliable treatment for localized renal cell carcinoma (RCC); however, nearly 50% of all RCC patients either have metastatic disease upon initial diagnosis or eventually develop metastatic disease [1], [2]. Unfortunately, RCC metastases lack sensitivity to standard treatments such as chemo- and radiotherapy. Immunotherapy has shown some promise, but currently only a subset of patients respond to this treatment and toxicity is a common complication. Thus, new forms of systemic therapy are desperately needed. One possible treatment target is the potent vasoconstrictor endothelin-1 (ET-1). Studies have demonstrated that ET-1 contributes to carcinogenesis as well as cancer progression in several malignancies, and the use of select endothelin receptor antagonists has exhibited potential as a cancer treatment. Endothelin-1 is a member of a family of vasoconstrictor peptides (ET-1, ET-2 and ET-3) initially isolated from vascular endothelial cells [3], [4], but now identified in diverse tissues and cell types [5], [6], [7], including the kidney [8], [9]. Human ET-1 is encoded by five exons within a 6836 CPTH2 hydrochloride pair region [4] on chromosome 6 [10]. The promoter region of the ET-1 gene has several sites for transcriptional regulation. Therefore, a variety of factors can induce transcription of the ET-1 gene, including angiotensin II, catecholamins, glucocorticoids, growth factors, some cytokines, insulin, low- and high-density lipoproteins, thrombin, hypoxia as well as shear stress [11], [12], [13], [14], [15], [16]. In addition, several factors inhibit transcription, such as atrial natriuretic hormone, nitric oxide, vasoactive intestinal peptide, prostaglandin E2 and prostacyclin [17], [18], [19], [20]. ET-1 is synthesized initially as preproendothelin 1 (PPET-1). A furin-like convertase further processes the PPET-1 protein to produce an intermediate 39-amino-acid prohormone, big ET-1. Big ET-1 can be secreted and circulate in the plasma; however, endothelin converting enzyme (ECE) must cleave big ET-1 to produce active protein. ET family members bind to two receptor subtypes: ETA and ETB. These G protein coupled heptahelical receptors exhibit different affinities for the ET family members: ETA preferentially binds ET-1 and ET-2 while ETB binds to all of the ETs with equal affinity [21], [22]. Activation of ETA can result in the induction of cell proliferation or survival pathways. While in many normal cells, the secretion and actions of ET-1 are regulated by ETB, including ET-1 clearance [23], inhibition of ET-1 secretion [17], and activation of pathways thought to counteract ETA-mediated signal transduction [24], [25], [26], [27]. In the kidney, a number of different tissue compartments, including blood vessels, glomerulus, tubules and collecting ducts, secrete ET-1. ETA and ETB receptors coexist in the same cells that secrete ET-1, but ETA and ETB also reside in juxtaglomerular and mesangial cells [28]. In polycystic kidney disease, ETA receptor expression is increased [29] and elevated ET-1 has been shown to contribute to renal ischemia and nephrotoxicity in animal models as well as in human disease [9], [30], [31], [32]. Indeed, several studies have demonstrated that ETA selective antagonists can protect against ischemia- and nephrotoxin-induced renal injury [33], [34], [35]. Stimulation of mesangial cells with ET-1 causes an autoinduction of a sixfold increase in ET-1 production through activation of the ETB receptor [36]. In general, the response to positive stimulus results in the transcription of ET-1 mRNA, with subsequent synthesis and secretion of ET-1 protein within minutes. The half-life of ET-1 mRNA is approximately 20min [4], [37], and the half-life of the protein in plasma is approximately 4–7min. Although, the half-life of mature ET-1 is short, an autocrine up-regulation mechanism in disease could induce elevated local concentrations in the kidney.