Marriott J B, Westby M, Cookson S, Guckian M, Goodbourn S, Muller G, Shire M G, Stirling D, Dalgleish A G
Department of Cellular and Molecular Sciences, St George's Hospital Medical School, London, United Kingdom.
J Immunol. 1998 Oct 15;161(8):4236-43.
The immunomodulatory drug thalidomide has been shown to be clinically useful in a number of situations due to its ability to inhibit TNF-alpha synthesis. However, its use is restricted by potentially serious side effects, including teratogenicity and neuorotoxicity; furthermore, insolubility may present problems in terms of systemic bioavailability. Recently, structural modifications of thalidomide have been designed enabling greatly enhanced anti-TNF-alpha activity in LPS-treated mice. In contrast to thalidomide (LPS-induced TNF-alpha IC50 approximately 200 microM in DMSO) and other analogs tested, one of these compounds, CC-3052 (IC50 approximately 1 microM in water), is water soluble. Furthermore, this analog exhibits increased stability in human plasma (t(1/2) approximately 17.5 vs 1.5 h for thalidomide) and appears to be nontoxic, nonmutagenic, and nonteratogenic. At pharmacologically active levels, cellular proliferation and LPS-induced IL-6 mRNA and IL-12p40 mRNA (as well as IL-1beta and IL-6 protein levels) in whole blood cultures were not affected; apparent inhibition of NK activity by CC-3052 was reversed upon addition of exogenous rTNF-alpha. In addition, IL-10 mRNA and protein levels were increased. These properties are consistent with results indicating inhibition of phosphodiesterase type IV activity by CC-3052. Furthermore, CC-3052 did not increase the degradation rate of macrophage TNF-alpha transcripts nor inhibit LPS-induced primary macrophage NF-kappaB activation. Taken together, the potency of selective TNF-alpha inhibition, water solubility, and increased plasma stability make CC-3052 an excellent candidate for further development and clinical evaluation for the treatment of TNF-alpha-mediated disease.
免疫调节药物沙利度胺已被证明由于其抑制肿瘤坏死因子-α（TNF-α）合成的能力，在多种情况下具有临床应用价值。然而，其使用受到潜在严重副作用的限制，包括致畸性和神经毒性；此外，不溶性可能在全身生物利用度方面带来问题。最近，已设计出沙利度胺的结构修饰物，在脂多糖（LPS）处理的小鼠中能极大增强抗TNF-α活性。与沙利度胺（在二甲基亚砜中LPS诱导的TNF-α半数抑制浓度（IC50）约为200微摩尔）和其他测试的类似物不同，其中一种化合物CC-3052（在水中IC50约为1微摩尔）是水溶性的。此外，这种类似物在人血浆中表现出更高的稳定性（半衰期约为17.5小时，而沙利度胺为1.5小时），并且似乎无毒、无致突变性和无致畸性。在药理活性水平下，全血培养中的细胞增殖以及LPS诱导的白细胞介素-6（IL-6）信使核糖核酸（mRNA）和白细胞介素-12p40 mRNA（以及IL-1β和IL-6蛋白水平）不受影响；添加外源性重组TNF-α后，CC-3052对自然杀伤细胞（NK）活性的明显抑制作用被逆转。此外，IL-10 mRNA和蛋白水平升高。这些特性与表明CC-3052抑制磷酸二酯酶IV型活性的结果一致。此外，CC-3052既没有增加巨噬细胞TNF-α转录本的降解速率，也没有抑制LPS诱导的原代巨噬细胞核因子-κB（NF-κB）激活。综上所述，选择性TNF-α抑制的效力、水溶性和血浆稳定性的提高使CC-3052成为进一步开发和临床评估用于治疗TNF-α介导疾病的优秀候选药物。
