Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is an antineoplastic agent that intercalates into DNA and alters topoisomerase II activity. Unfortunately, this compound displays a number of adverse properties. Therefore, to investigate new ellipticine-based compounds for their potential as topoisomerase II-targeted drugs, we synthesized two novel derivatives, N-methyl-5-demethyl ellipticine (ET-1) and 2-methyl-N-methyl-5-demethyl ellipticinium iodide (ET-2). As determined by DNA decatenation and cleavage assays, ET-1 and ET-2 act as catalytic inhibitors of human topoisomerase IIα and are both more potent than the parent compound. Neither compound impairs the ability of the type II enzyme to bind its DNA substrate. Finally, the potency of ET-1 and ET-2 as catalytic inhibitors of topoisomerase IIα appears to be related to their ability to intercalate into the double helix.

2012-10-01·Life Sciences3区 · 医学

Endothelin-1 and -2: Two amino acids matter

3区 · 医学

Article

作者: Matthijs G Compeer ; Tilman M Hackeng ; Dennis P L Suylen ; Jo G R De Mey

AIMSEndothelin-1 (ET-1) and endothelin-2 (ET-2; Trp(6)Leu(7)ET-1) are expressed by different cell types, but are considered to display identical pharmacological properties on endothelin receptors. We studied agonist-dependent aspects of endothelin(A) (ET(A))-receptor function and the importance of amino acids 6 and 7 of ET-1 and ET-2 in this respect.MAIN METHODSWe used isolated rat mesenteric resistance arteries in wire myographs, in a setting that minimizes influences of endothelium and sensorimotor nerves, to study arterial smooth muscle ET(A)-receptor-mediated vasomotor responses, to ET-1, ET-2 and chimeras thereof (Trp(6)ET-1 and Leu(7)ET-1).KEY FINDINGSET-1 and ET-2 cause arterial contractions with comparable sensitivities and maximal responses. BQ123 (ET(A)-antagonist) reduces sensitivity to ET-1 more potently than that to ET-2 (pK(B): 7.1 ± 0.2 versus 5.6 ± 0.4). However, 1 μM BQ123 relaxes maximal contractile responses to ET-2 more markedly than those to ET-1. Leu(7)ET-1 is a contractile agonist with lower potency and similar maximal effect compared to ET-1 and greater sensitivity to BQ123 than ET-2. Up to 256 nM Trp(6)ET-1 did not cause contraction and did not antagonize arterial responses to ET-1.SIGNIFICANCEArterial smooth muscle ET(A)-receptor function displays agonist-dependent aspects. This involves roles of amino acids on position 6 and 7 of the endothelin sequence. Agonist-dependent pathologies may benefit from the design of specific, agonist-selective ET-receptor antagonists.

2005-01-01·Roczniki Akademii Medycznej w Bialymstoku (1995)

The cumulative effect of nuclear factor-kappaB (NF-kappaB) inhibition and endothelins in early cerulein-induced acute pancreatitis in rats.

Article

作者: Wróblewski, E ; Dabrowski, A ; Andrzejewska, A ; Nowak, K ; Długosz, J W

PURPOSETo assess effects of NF-kappaB activation inhibitor (pyrrolidine dithiocarbamate--PDTC) alone or with endothelins (ET-1, ET-2, ET-3) in early course of cerulein-induced acute pancreatitis (AP) in rats.MATERIAL AND METHODSAfter 4 h of AP in Wistar rats, treated with PDTC 10 or 40 mg/kg or with PDTC 10 mg/kg and ET-1, ET-2 or ET-3, 0.5 or 1.0 nmol/kg twice i.p. in 1 h interval, free active trypsin (FAT), total potential trypsin (TPT) and lipase in 12000 x g supernatants of pancreatic homogenates, plasma alpha-amylase and histological changes were assayed. %FAT/TPT was an index of trypsinogen activation.RESULTS%FAT/TPT significantly increased to 12.42 +/- 2.14%, lipase to 5.51 +/- 0.84 U/mg protein and alpha-amylase to 28.5 +/- 5.61 U/mL in AP vs 1.96 +/- 0.31%, 1.29 +/- 0.11 U/mg and 5.80 +/- 1.38 U/ml in healthy control. Higher dose PDTC attenuated trypsinogen activation to 3.01 +/- 0.53% and alpha-amylase to 15.3 +/- 1.38. PDTC and ET-1 attenuated %FAT/TPT to 2.55 +/- 0.18% with lower and 2.34 +/- 0.44% with higher dose. ET-3 was less effective than ET-1: 6.76 +/- 0.46% with lower dose. Lower doses of ET-1 and ET-2 with PDTC, diminished lipase activity to 2.60 +/- 0.36 and 2.94 +/- 0.33.CONCLUSIONSCumulative attenuation of trypsinogen activation after lower dose of PDTC and ET-1 approximated the effect of higher dose of PDTC. Additional effect of ET-3 was weaker than ET-1, and ET-2 was ineffective in this respect. The combination of this NF-kappaB activation inhibitor and ET-1 could be beneficial in early course of edematous AP by attenuating of trypsinogen activation. However, it should be treated with caution because of some unfavorable effects on histological scores of pancreatic injury.

项与 ET-02(Eirion Therapeutics) 相关的新闻（医药）

2024-07-01

·PRNewswire

Eirion Therapeutics Announces Initiation of First-in-Human Clinical Trial Evaluating Topical ET-02 for the Treatment of Androgenic Alopecia

WOBURN, Mass., July 1, 2024 /PRNewswire/ -- Eirion Therapeutics Inc. announced today that the first participant has been enrolled in a Phase 1 clinical trial to evaluate the safety of the patented topical pharmaceutical ET-02 for the treatment of androgenic alopecia (age-related hair loss). This double-blind, placebo-controlled study is designed to determine the safety of ET-02 for once daily treatment over 28 days. The study is expected to recruit approximately 24 subjects at three investigation centers in the United States. ET-02 has a novel mechanism of action which targets returning hair follicle stem cells that have become defective and / or inactive in men suffering from age-related hair loss to normal activity and function. Hair follicle stem cells are known to be the "master control switches" for hair growth. By returning stem cells to normal activity and function, the expectation is that hair can be grown normally again. Because ET-02 directly addresses what the Company believes is the fundamental cause of androgenic alopecia, the Company expects this new treatment has the potential to be significantly more effective than existing treatments which have no known direct impact on hair follicle stem cells. "Given its postulated mechanism of action, ET-02 represents a potentially substantial advancement over commercially available pharmaceuticals for the treatment of androgenic alopecia," said Jerry Shapiro, MD, a leading expert on the treatment of hair loss and Professor of Dermatology at New York University Grossman School of Medicine. "This Phase 1 safety study is an important first step in evaluating ET-02. Assuming all goes well, this study will lead to a Phase 2 study evaluating ET-02's efficacy." Jon Edelson, MD, CEO and President of Eirion, added, "A controlled pre-clinical study of ET-02 treating 90 human scalp tissue grafts from men who have intermediate-stage androgenic alopecia demonstrates this pharmaceutical's potential to restore hair growth and return hair follicles to normal structure and function. Because of ET-02's unique mechanism of action, we believe that ET-02 has the potential to not only treat androgenic alopecia but prevent it." Unlike some other commercially available treatments, ET-02 does not target hormonal pathways and is not expected to have the side effects associated with such treatments, which include sexual dysfunction. The Company believes that ET-02 also has the potential to treat and prevent hair greying by impacting the stem cell that controls hair color which is called the melanocyte stem cell. The Company plans to pursue treatment of this indication in the future. ET-02 is the third product currently in development by Eirion. ET-01 topical neuromodulator is in Phase 2 and has been studied in clinical trials with over 750 subjects in aggregate. AI-09 next-generation, ready-to-use liquid injectable neuromodulator has been studied in 96 subjects in a Phase 1 - 2 clinical trial. "ET-02 is a highly complementary product to our two other aesthetic bio-pharmaceutical products in development, which are both potential treatments for facial wrinkles. Taking these three product candidates together, Eirion has built an exciting and robust pipeline for aesthetic medicine innovation," commented Dr. Edelson. About Eirion Therapeutics, Inc. Eirion Therapeutics, Inc. is a privately held, clinical stage biopharmaceutical company that is developing next-generation prescription products for aesthetic dermatology. Eirion currently has a rich pipeline of products focusing on treatments for wrinkles, primary axillary hyperhidrosis, androgenic alopecia, and hair greying. In the future, Eirion plans to pursue additional indications that address other major unmet clinical needs for physicians and their patients. To learn more about Eirion, please visit: Media Contact Megan Driscoll EvolveMKD [email protected] SOURCE Eirion Therapeutics, Inc.

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100 项与 ET-02(Eirion Therapeutics) 相关的药物交易

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