VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid.
VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid.
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DOI：
10.1016/j.bmc.2013.02.009
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发表时间：
2013-04-15
影响因子：
3.5
通讯作者：
McCall JM
中科院分区：
文献类型：
--
作者：
Reeves EKM;Hoffman EP;Nagaraju K;Damsker JM;McCall JM
糖皮质激素（21-氨基类固醇）的Δ 9，11修饰已被开发为用于保护细胞免受损伤（脂质过氧化; lazaroids）和抑制新血管形成（anecortave）的药物。开发这些化合物的部分基本原理是由于Δ 9，11修饰而失去糖皮质激素受体结合，从而避免了与糖皮质激素和盐皮质激素受体结合相关的许多免疫抑制活性和有害副作用特征。我们最近证实，醋酸阿奈可他及其21-羟基类似物（VBP 1）确实显示出糖皮质激素和盐皮质激素受体结合活性，糖皮质激素受体有效易位至细胞核。我们的结论是，Δ 9，11类固醇显示出新的抗炎特性，保留了NF-κB抑制，但失去了有害的糖皮质激素副作用。这方面的证据是在慢性肌肉炎症的临床前试验中发现的。在这里，我们描述了一个旨在优化Δ 9，11化学的药物开发计划。在体外筛选中测试了20种Δ 9，11衍生物的NF-κB抑制和GR易位至细胞核以及低细胞毒性。选择VBP 15作为先导化合物是因为其与泼尼松和地塞米松类似的有效NF-κB抑制和GR易位、缺乏反式激活特性以及良好的生物利用度。Phamacoketrin与传统糖皮质激素药物相似，终末半衰期为0.35 h（小鼠）、0.58 h（大鼠）、5.42 h（犬），生物利用度为74.5%（小鼠）和53.2%（犬）。代谢稳定性显示，在人、犬和猴肝微粒体中，VBP 6和VBP 15在1 h时的残留量≥80%。溶解度、渗透性和血浆蛋白结合率均在可接受限度内。VBP 15在三个人肝细胞供体中中度诱导CYP 3A 4（24-42%），与其他类固醇相似。VBP 15目前正在开发用于治疗杜氏肌营养不良症。
Δ9,11 modifications of glucocorticoids (21-aminosteroids) have been developed as drugs for protection against cell damage (lipid peroxidation; lazaroids) and inhibition of neovascularization (anecortave). Part of the rationale for developing these compounds has been the loss of glucocorticoid receptor binding due to the Δ9,11 modification, thus avoiding many immunosuppressive activities and deleterious side effect profiles associated with binding to glucocorticoid and mineralocorticoid receptors. We recently demonstrated that anecortave acetate and its 21-hydroxy analog (VBP1) do, in fact, show glucocorticoid and mineralocorticoid receptor binding activities, with potent translocation of the glucocorticoid receptor to the cell nucleus. We concluded that Δ9,11 steroids showed novel anti-inflammatory properties, retaining NF-κB inhibition, but losing deleterious glucocorticoid side effect profiles. Evidence for this was developed in pre-clinical trials of chronic muscle inflammation. Here, we describe a drug development program aimed at optimizing the Δ9,11 chemistry. Twenty Δ9,11 derivatives were tested in in vitro screens for NF-κB inhibition and GR translocation to the nucleus, and low cell toxicity. VBP15 was selected as the lead compound due to potent NF-κB inhibition and GR translocation similar to prednisone and dexamethasone, lack of transactivation properties, and good bioavailability. Phamacokinetics were similar to traditional glucocorticoid drugs with terminal half-life of 0.35 h (mice), 0.58 h (rats), 5.42 h (dogs), and bioavailability of 74.5% (mice), and 53.2% (dogs). Metabolic stability showed ≥80% remaining at 1 h of VBP6 and VBP15 in human, dog, and monkey liver microsomes. Solubility, permeability and plasma protein binding were within acceptable limits. VBP15 moderately induced CYP3A4 across the three human hepatocyte donors (24–42%), similar to other steroids. VBP15 is currently under development for treatment of Duchenne muscular dystrophy.
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影响因子：
5.6
作者：
Baudy AR;Saxena N;Gordish H;Hoffman EP;Nagaraju K
通讯作者：
Nagaraju K
DOI：
10.1016/j.pmr.2012.08.003
发表时间：
2012-11-01
影响因子：
1.7
作者：
Hoffman, Eric P.;Reeves, Erica;Bushby, Kate
通讯作者：
Bushby, Kate
影响因子：
13.7
作者：
Russell, S;Boldt, HC;Beasley, C
通讯作者：
Beasley, C
DOI：
10.1159/000336676
发表时间：
2012-01-01
期刊：
NEW TREATMENTS IN NONINFECTIOUS UVEITIS
影响因子：
--
作者：
LeHoang, Phuc
通讯作者：
LeHoang, Phuc
影响因子：
4.1
作者：
Bracken, MB;Shepard, MJ;Young, W
通讯作者：
Young, W