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Ruboxistaurin Sale

(Synonyms: LY333531) 目录号 : GC63177

Ruboxistaurin (LY333531) HCl is a β-specific protein kinase C inhibitor. It competitively and reversibly inhibits PKCβ1 and PKCβ2 with IC50 values of 4.7 and 5.9 nM respectively.

Ruboxistaurin Chemical Structure

Cas No.:169939-94-0

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10mM (in 1mL DMSO)
¥1,278.00
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5mg
¥1,239.00
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10mg
¥2,240.00
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25mg
¥4,480.00
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50mg
¥7,175.00
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产品描述

Ruboxistaurin (LY333531) HCl is a β-specific protein kinase C inhibitor. It competitively and reversibly inhibits PKCβ1 and PKCβ2 with IC50 values of 4.7 and 5.9 nM respectively.

LY333531 strikingly decreases the chance of HUVEC survival and the effect of LY333531 on apoptotic cell death in HUVEC significantly increases compared with the AGEs group. Blockade of PKC-beta up-regulates the expression of Bax and Bad proteins and down-regulates the expression of Bcl-2 protein. Moreover, LY333531 reduces the ratio of Bcl-2/Bax. LY333531 can further prompt AGEs-induced endothelial cells apoptosis. The increased expression of Bax, Bad and decreased expression of Bcl-2 and Bcl-2/Bax ratio are associated with the apoptotic process[3].

LY333531 treatment (for a duration of 4 weeks) prevents excessive PKCb2 activation and attenuates cardiac diastolic dysfunction in rats with streptozotocin-induced diabetes. LY333531 suppresses the decreased expression of myocardial NO, Cav-3, phosphorylated (p)-Akt, and p-eNOS and also mitigates the augmentation of O2-, nitrotyrosine, Cav-1, and iNOS expression[2].

[1] Jirousek MR, et al. J Med Chem. 1996, 39(14):2664-71. [2] Lei S, et al. Diabetes. 2013, 62(7):2318-28. [3] Wang SS, et al. Pharmazie. 2011, 66(11):881-7.

Chemical Properties

Cas No. 169939-94-0 SDF
别名 LY333531
分子式 C28H28N4O3 分子量 468.55
溶解度 DMSO : 50 mg/mL (106.71 mM; ultrasonic and warming and heat to 60°C) 储存条件 Store at -20°C
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1 mM 2.1342 mL 10.6712 mL 21.3424 mL
5 mM 0.4268 mL 2.1342 mL 4.2685 mL
10 mM 0.2134 mL 1.0671 mL 2.1342 mL
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Research Update

Ruboxistaurin

Drugs Today (Barc) 2006 Sep;42(9):577-85.PMID:17028667DOI:10.1358/dot.2006.42.9.996566.

Ruboxistaurin is a potent and specific inhibitor of the beta isoform of protein kinase C. Overactivation of protein kinase C has been demonstrated in patients with type 2 diabetes, and is postulated to play a major role in the pathogenesis of diabetic microvascular complications, which include diabetic retinopathy, neuropathy and nephropathy. The role of protein kinase C in promoting tissue injury in patients with diabetes, and the pharmacologic and clinical studies illustrating the potential of Ruboxistaurin to reduce the burden of diabetic microvascular complications will be discussed in this article.

Ruboxistaurin: LY 333531

Drugs R D 2007;8(3):193-9.PMID:17472415DOI:10.2165/00126839-200708030-00007.

Ruboxistaurin, an orally active protein kinase C beta (PKC beta) inhibitor, is a macrocyclic bisindolylmaleimide compound under development by Eli Lilly with potential as a therapy for diabetic macular oedema and other diabetic angiopathies, including diabetic retinopathy, diabetic peripheral neuropathy and diabetic nephropathy. Ruboxistaurin is awaiting approvals in the US and Europe for the treatment of diabetic retinopathy. Eli Lilly and Alcon entered into a long-term agreement to co-promote Ruboxistaurin in the US and Puerto Rico for diabetic retinopathy. The agreement is subject to the US FDA's approval of the agent for this indication. Under the terms of the agreement, Alcon will assume primary responsibility for promotion to eye specialists including retinal specialists and general ophthalmologists, while Eli Lilly will be targeting endocrinologists and physicians. Subject to approval in the US, Eli Lilly will receive milestone and marketing payments from Alcon. Alcon in turn will receive compensation based on product sales. In December 2003, Eli Lilly signed a joint development and co-marketing agreement with Takeda Chemical Industries for Ruboxistaurin in the Japanese market. Under the terms of the agreement, Eli Lilly Japan and Takeda will jointly develop Ruboxistaurin in Japan, will file an NDA for diabetic peripheral neuropathy and diabetic retinopathy, and subsequently will market the drug in Japan. Ruboxistaurin was submitted for approval in Europe in the second quarter of 2006. The agent is also in phase II studies for the treatment of diabetic maculopathy (macular retinopathy) in Japan. Data from a phase III, 3-year study of Ruboxistaurin in patients with moderate to severe diabetic retinopathy showed that Ruboxistaurin markedly reduced the risk of sustained vision loss compared with placebo. This multicentre, randomised study, named PKC-DRS2 (Protein Kinase C-Diabetic Retinopathy Study 2), was conducted at 70 clinical sites and involved 685 patients with diabetic retinopathy. The agent is also in a phase II study in the US, Canada and Europe in patients with clinically significant macular oedema. The trial (B7A-MC-MBCU), which will evaluate oral administration of the drug using optical coherence tomography over a period of 18 months, is expected to enrol approximately 220 patients. This randomised, double-blind, placebo-controlled study was initiated in August 2005 and is expected to be completed in March 2008. Previously, results of the PKC-Diabetic Retinopathy Study (PKC-DRS) showed that Ruboxistaurin at a dose of 32 mg/day has potential to reduce the risk of moderate vision loss especially in patients with diabetic macular oedema. This phase III, randomised, double-blind, multidose study in 252 patients with type 1 and type 2 diabetes receiving Ruboxistaurin or placebo for 3-4 years evaluated the safety of the agent and its effect on progression of diabetic retinopathy, moderate vision loss and sustained moderate vision loss. The study was conducted at Joslin Diabetes Center and at centres in the US, Canada, Denmark, The Netherlands and the UK. In 2004, Eli Lilly presented new analysis of previously reported data for Ruboxistaurin in diabetic macular oedema indicating that Ruboxistaurin has the potential to decrease the progression of diabetic macular oedema involving the center of the macula. Positive results from the PKC Beta Inhibitor Diabetic Macular Edema (PKC-DMES) trial were reported in 2003. Eli Lilly expected to file for approval of Ruboxistaurin for the treatment of diabetic peripheral neuropathy in the US and Europe in 2005. However, no development was reported for this indication. On 15 March 2007, Eli Lilly withdrew its marketing authorisation application for Ruboxistaurin for diabetic retinopathy filed with EMEA in May 2006. Its current development status in the EU is unclear at this stage.

Update of pathophysiology and management of diabetic kidney disease

J Formos Med Assoc 2018 Aug;117(8):662-675.PMID:29486908DOI:10.1016/j.jfma.2018.02.007.

Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in patients with diabetes mellitus and the leading cause of end-stage renal disease in the world. The most characteristic marker of DKD is albuminuria, which is associated with renal disease progression and cardiovascular events. Renal hemodynamics changes, oxidative stress, inflammation, hypoxia and overactive renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis of DKD, and renal fibrosis plays the key role. Intensified multifactorial interventions, including RAAS blockades, blood pressure and glucose control, and quitting smoking, help to prevent DKD development and progression. In recent years, novel agents are applied for preventing DKD development and progression, including new types of glucose-lowering agents, pentoxifylline, vitamin D analog paricalcitol, pyridoxamine, Ruboxistaurin, soludexide, Janus kinase inhibitors and nonsteroidal minerocorticoid receptor antagonists. In this review, recent large studies about DKD are also summarized.

Ruboxistaurin, a protein kinase C beta inhibitor, as an emerging treatment for diabetes microvascular complications

Ann Pharmacother 2005 Oct;39(10):1693-9.PMID:16160002DOI:10.1345/aph.1E572.

Objective: To review current clinical data regarding the pharmacologic actions of Ruboxistaurin (LY333531) mesylate, an inhibitor of protein kinase C (PKC) beta, and its role to potentially reduce the development and/or the progression of diabetic microvascular complications. Data sources: Primary literature was obtained via a MEDLINE search (1966-August 2004) and through review of pertinent abstracts and presentations at major medical meetings. Study selection and data extraction: Literature relevant to PKC physiology, the pharmacokinetics of Ruboxistaurin, and data evaluating the use of Ruboxistaurin in treating diabetic microvascular complications in human and relevant animal models was reviewed. Data synthesis: PKC is part of a group of intracellular signaling molecules activated in response to various specific hormonal, neuronal, and growth factor stimuli. Hyperglycemia leads to PKC beta 1 and 2 isoform activation, which experimentally has been shown to contribute to the development and progression of diabetic microvascular complications (retinopathy, nephropathy, neuropathy) through various biochemical mechanisms. Animal and/or human studies using Ruboxistaurin mesylate, a novel, highly selective inhibitor of PKC beta, have shown delay in the progression and, in some cases, reversal of diabetic retinopathy, nephropathy, and neuropathy. Conclusions: Ruboxistaurin mesylate, by inhibiting excessive activation of certain PKC isoforms, has the potential to reduce the burden of microvascular complications for patients with diabetes.

Ruboxistaurin mesilate hydrate for diabetic retinopathy

Drugs Today (Barc) 2009 Apr;45(4):269-74.PMID:19499092DOI:10.1358/dot.2009.45.4.1354195.

Diabetic retinopathy remains a major worldwide cause of preventable blindness. The beta isoform of protein kinase C (PKC) may play an important role in the pathogenesis of this disorder. Ruboxistaurin mesylate hydrate is an orally bioavailable, highly-specific inhibitor of PKC beta, which has shown some efficacy in several large, multicenter, randomized clinical trials. The U.S. Food and Drug Administration issued an approvable letter for Ruboxistaurin in 2006, but at this time the medication is not available for routine clinical use.