美国国立卫生研究院的科学家合成药物在小鼠限制肝纤维化

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NIH scientists synthesize drug that limits liver fibrosis in mice
by Oliver Worsley | Aug 3, 2016 6:58am
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Liver fibrosis is a progressive scarring of the liver brought on by chronic alcoholism, viral hepatitis, obesity or diabetes. The condition could lead to cirrhosis and cancer of the liver. Despite its prevalence, there is no mainstay treatment to prevent scarring.

Now researchers at the National Institutes of Health (NIH) have reported developing a drug that limits liver fibrosis in mice. The findings have been published online in the journal JCI Insight.

The drug was synthesized using the chemical structure of ibipinapant--a brain-penetrating CB-1 receptor antagonist--as the backbone for the drug with two changes to it.

First they altered the structure to lower the amount that can pass the blood-brain barrier. This avoided any psychiatric side effects that limit the use of the original drug, ibipinapant, in the clinic. Secondly, they added a molecular group that inhibits the molecule iNOS, an enzyme responsible for promoting inflammation.

“Inducible nitric oxide synthase, or iNOS, is an enzyme that has been shown to play a fundamental role in liver fibrosis pathology and is a potential target for fibrosis therapy,” said George Kunos, who heads the study, in an NIH news release. “It is also an important factor in alcoholic liver disease, viral hepatitis, fatty liver disease, and other pathologies that promote liver fibrosis.”

In two well-established models of liver fibrosis, the NIH group found that their compound worked better to reduce fibrosis than using either CB-1 receptor inhibition or iNOS delivery alone.

Preliminary studies in their lab demonstrate no “off target” effects that might give rise to side effects, at least in their animal models. Kunos admits that the compound will need to be further tested in animal models before it's taken forward to clinical trials.

StephenW

美国国立卫生研究院的科学家合成药物在小鼠限制肝纤维化
由奥利弗·沃斯利| 2016年8月3日上午06时58分
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肝纤维化是慢性酒精中毒，病毒性肝炎，肥胖症或糖尿病带来的肝脏的渐进疤痕。的条件可能导致肝硬化和癌症。尽管其患病率，没有支柱治疗，防止疤痕。

现在，研究人员在健康（NIH）全国学院已经发展报告在小鼠中限制了肝纤维化的药物。该研究结果已在杂志JCI洞察网上公布。

脑穿透的CB-1受体拮抗剂 - - 为骨干与两个变化给它的药物的药物使用ibipinapant的化学结构合成。

首先，他们改变了结构，降低可通过血 - 脑屏障的量。这避免了任何精神病副作用限制使用原药，ibipinapant，在诊所。其次，他们补充说，抑制iNOS的分子，负责促进炎症的酶的分子团。

“诱导型一氧化氮合酶，或iNOS的，是已被证明在肝纤维化的病理基础性作用，是肝纤维化治疗的潜在靶点酶，”乔治Kunos，谁负责的研究中，美国国立卫生研究院的新闻发布会上说。 “这也是在酒精性肝病，病毒性肝炎，脂肪肝疾病，以及促进肝纤维化其它病理学的重要因素。”

在肝纤维化的两个成熟的车型，NIH的研究小组发现，他们的工作化合物，更能减少比使用或者CB-1受体抑制iNOS的或单独交付纤维化。

在他们的实验室初步研究表明没有“脱靶”效应可能引起副作用，至少在其的动物模型。 Kunos承认，化合物将需要它采取着的临床试验之前，在动物模型中进一步测试。

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