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Compound E Sale

(Synonyms: N-[(1S)-2-[[(3S)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂卓-3-基]氨基]-1-甲基-2-氧代乙基]-3,5-二氟苯乙酰胺,γ-Secretase-IN-1) 目录号 : GC33118

An inhibitor of γ-secretase

Compound E Chemical Structure

Cas No.:209986-17-4

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10mM (in 1mL DMSO)
¥3,928.00
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1mg
¥1,120.00
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5mg
¥3,640.00
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10mg
¥6,440.00
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25mg
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实验参考方法

Cell experiment:

The breast cancer cell lines MDA-MB-231, T47D, and MCF-7 are treated with Compound E at concentrations in the range 0.01-50 μM for 48 h and their viability is determined using a Coulter counter[1].

References:

[1]. Beher D, et al. Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology. J Biol Chem. 2001 Nov 30;276(48):45394-402.
[2]. Rasul S, et al. Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells. Br J Cancer. 2009 Jun 16;100(12):1879-88.

产品描述

γ-Secretase is a multimeric aspartyl protease that regulates signaling pathways by proteolytically cleaving substrates, abrogating or releasing signaling molecules.1 Two well-known substrates are the carboxyl-terminal fragments (CTFs) of the receptor Notch, which has key roles in development, and that of amyloid precursor protein (APP), which is important in Alzheimer’s disease.1 Compound E is a potent, cell-permeable, and selective inhibitor of γ-secretase, blocking the cleavage of both APP and Notch CTFs with IC50 values of ~0.3 nM.2,3,4 Compound E induces neuronal differentiation, impairs ovarian folliculogenesis, and suppresses thymocyte development by preventing Notch activation by γ-secretase.5,6,7

1.Jurisch-Yaksi, N., Sannerud, R., and Annaert, W.A fast growing spectrum of biological functions of γ-secretase in development and diseaseBiochim. Biophys. Acta1828(12)2815-2827(2013) 2.Seiffert, D., Bradley, J.D., Rominger, C.M., et al.Presenilin-1 and -2 are molecular targets for γ-secretase inhibitorsJ. Biol. Chem.275(44)34086-34091(2000) 3.Beher, D., Wrigley, J.D.J., Nadin, A., et al.Pharmacological knock-down of the presenilin 1 heterodimer by a novel g -secretase inhibitor. Implications for presenilin biologyJ. Biol. Chem.276(48)45394-45402(2001) 4.Zhao, G., Mao, G., Tan, J., et al.Identification of a new presenilin-dependent ζ-cleavage site within the transmembrane domain of amyloid precursor proteinJ. Biol. Chem.279(49)50647-50650(2004) 5.Ferrari-Toninelli, G., Bonini, S.A., Uberti, D., et al.Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cellsNeuro. Oncol.12(12)1231-1243(2010) 6.Jovanovic, V.P., Sauer, C.M., Shawber, C.J., et al.Intraovarian regulation of gonadotropin-dependent folliculogenesis depends on notch receptor signaling pathways not involving Delta-like ligand 4 (Dll4)Reprod. Biol. Endocrinol.1143(2013) 7.Doerfler, P., Shearman, M.S., and Perlmutter, R.M.Presenilin-dependent γ-secretase activity modulates thymocyte developmentProc. Natl. Acad. Sci. USA98(16)9312-9317(2001)

Chemical Properties

Cas No. 209986-17-4 SDF
别名 N-[(1S)-2-[[(3S)-2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂卓-3-基]氨基]-1-甲基-2-氧代乙基]-3,5-二氟苯乙酰胺,γ-Secretase-IN-1
Canonical SMILES FC1=CC(CC(N[C@@H](C)C(N[C@@H]2C(N(C)C(C=CC=C3)=C3C(C4=CC=CC=C4)=N2)=O)=O)=O)=CC(F)=C1
分子式 C27H24F2N4O3 分子量 490.5
溶解度 DMSO: 100 mg/mL (203.87 mM) 储存条件 Store at -20°C, sealed storage, away from moisture and light
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Research Update

The History of Cortisone Discovery and Development

Rheum Dis Clin North Am 2016 Feb;42(1):1-14, vii.PMID:26611547DOI:10.1016/j.rdc.2015.08.001.

Philip Hench, Edward Kendall, and Tadeus Reichstein received the Nobel Prize in medicine and physiology in 1950 for their "investigations of the hormones of the adrenal cortex." Hench and Kendall took Compound E from the laboratory to the clinic to the Nobel Prize in a span of 2 years. This article examines the paths that led to the day when the first rheumatoid arthritis patient received cortisone, and from there to the 1950 Nobel Prize ceremony. The aftermath of this achievement is also discussed. Although there have been significant advances in corticosteroid preparations and use since 1950, the side effects remain daunting.

The mechanism of action of 17-hydroxy-11-dehydrocorticosterone (Compound E) and of the adrenocorticotropic hormone in experimental hypersensitivity in rabbits

J Exp Med 1951 Aug;94(2):139-70.PMID:14861375DOI:10.1084/jem.94.2.139.

The concurrent administration of Compound E at a daily dosage of 2 mg. per kg. to rabbits receiving daily intracutaneous injections of crystalline egg albumin markedly inhibited the development of anaphylactic hypersensitivity of the Arthus type. ACTH, when given at a similar dosage, produced a much less marked effect. Both hormones suppressed circulating antibody and as with the Arthus reaction, the suppression produced by Compound E was much greater than that obtained with ACTH. When treatment with Compound E was started following sensitization, there was a rapid decline in circulating antibody and, if the pretreatment serum antibody was low, there was also a progressive decrease in skin reactivity, becoming negative after 5 days of treatment. When the pretreatment serum antibody concentration was great, so that by the termination of treatment the antibody concentration was still above the level ordinarily sufficient for a maximal skin response, the Arthus reaction was unaffected by treatment. These considerations as well as the failure of Compound E to inhibit the systemic passive Arthus reaction suggest that the inhibitory effect of Compound E and ACTH on the development of experimental hypersensitivity results from the hormonal reduction of circulating antibody. Treatment with Compound E had no effect on the rate of disappearance of circulating antibody in the passively immunized rabbit. This finding suggests that ACTH and Compound E reduce circulating antibody by inhibiting antibody formation rather than by promoting antibody destruction. The question is raised as to whether the marked lymphoid atrophy produced by these hormones may be related to the interference with antibody production.

Diamonds are forever: the cortisone legacy

J Endocrinol 2007 Oct;195(1):1-6.PMID:17911391DOI:10.1677/JOE-07-0309.

The year 1946 was not only the year that the Society for Endocrinology was founded, but also the year that Edward Kendall's Compound E (cortisone) was first synthesised by Louis Sarett. By 1948, sufficient quantities of Compound E were available for the rheumatologist Philip Hench to test it successfully for the first time in a patient with rheumatoid arthritis. It was immediately hailed as a 'wonder drug' and was shown to be effective in a number of inflammation-associated conditions, most notably rheumatoid arthritis. The subsequent development of endocrinology as a discipline is inextricably linked to the chemistry, biology and medicine of antiinflammatory glucocorticoids. Sixty years after the first chemical synthesis of cortisone, corticosteroids remain among the top ten most commonly used prescription and over the counter drugs. Basic and clinical studies of glucocorticoid biosynthesis, metabolism and action have trail-blazed developments in endocrinology ever since. This article surveys the extraordinary cortisone timeline, from first synthesis until now. The concluding scientific message is that intracrine metabolism of cortisone to cortisol via 11beta hydroxysteroid dehydrogenase type 1 likely sustains local amplification of glucocorticoid action at sites of inflammation throughout the body. The broader message is that the discovery of Compound E by Kendall (basic scientist), its large-scale synthesis by Sarett (industrial chemist) and its therapeutic application by Hench (rheumatologist) serves as a paradigm for modern translational medicine. It is concluded that endocrinology will remain a force in health and disease if it continues to evolve sans frontières at the basic/applied/clinical science interface. A challenge for the Society for Endocrinology is to ensure this happens.

Compound f: the history of hydrocortisone and hand surgery

J Hand Surg Am 2013 Apr;38(4):774-8.PMID:23403170DOI:10.1016/j.jhsa.2012.12.025.

Hydrocortisone (cortisol) is used daily in the practice of medicine and hand surgery. It has an effective use in a number of orthopedic conditions, including tendinitis, tenovaginitis, bursitis, carpal tunnel syndrome, and joint inflammation. But are surgeons aware of how this important pharmaceutical agent was discovered and prepared for clinical trial and who was responsible for its first clinical application? How did medical doctors determine that, like penicillin, cortisone and its derivative hydrocortisone would have such a life-changing effect on certain medical conditions? The purpose of this review is to relate the story of the development of cortisone (Compound E) and hydrocortisone (Compound F) and how both influenced the practice of hand surgeons in the treatment of rheumatoid arthritis and related inflammatory conditions. This history of cortisone and hydrocortisone also relates to the importance of partnership between physician and research scientist and of the principle at Mayo Clinic that the only concern--or the first concern--is the concern for the patient.

Special issue-before translational medicine: laboratory clinic relations lost in translation? Cortisone and the treatment of rheumatoid arthritis in Britain, 1950-1960

Hist Philos Life Sci 2019 Nov 7;41(4):54.PMID:31701313DOI:10.1007/s40656-019-0269-7.

Cortisone, initially known as 'Compound E' was the medical sensation of the late 1940s and early 1950s. As early as April 1949, only a week after Philip Hench and colleagues first described the potential of 'Compound E' at a Mayo Clinic seminar, the New York Times reported the drug's promise as a 'modern miracle' in the treatment of rheumatoid arthritis (RA). Given its high profile, it is unsurprising that historians of medicine have been attracted to study the innovation of cortisone. It arrived at the end of a decade of 'therapeutic revolutions', kicked off by penicillin transforming the treatment of bacterial infections and ending with hopes of a revolution in the treatment of non-infectious, chronic inflammatory diseases. Despite these studies of cortisone's introduction, few historians have taken the story forward and considered how cortisone was adopted and adapted into clinical practice. This article tells the longer of how the drug and its derivatives were taken from research laboratories and integrated into clinical practice; what has in recent decades become known as translational medicine (TM). In exploring cortisone's first decade in Britain, we focus specifically on its role in the treatment of RA. Our approach is always to consider cortisone's use in the context of other treatments available to clinicians, and at local and national institutional settings. We do not discuss the many other therapeutic uses of cortisone, which ranged for topical applications for skin diseases to the management of cancers, especially childhood leukaemia, nor do we discuss its close analogue ACTH-AdenoCorticoTropic Hormone. We think there are lessons in our study for TM policies today.