摘要
背景:近年来,尽管肺动脉高压的治疗已经取得了重大进展,这仍然是一个严重预后不良的疾病,并且寻找新的药物仍然要优先。目前补救措施主要解决血管收缩剂/肺循环血管扩张的失衡,尽管疾病的原因只是适度的影响。最近,受体和非受体激酶在肺动脉高压中的作用已经出现,这些目标被广泛认为是新治疗策略的发展。本文论述了专利小分子靶向激酶参与增殖/凋亡失衡,通常出现在肺动脉高压中。 方法:文献研究发明使用Espacenet和Sci-Finder数据库,以2010-2015年,肺动脉高压和激酶作为研究范围查询。只有发表的英文专利符合。每个专利定性分析的内容用作检查报告的化合物,研究执行和结果讨论。 结果:审查包括大约30个程序。此外,为了说明病理生理疾病和目标机制,大约四十额外的论文报告被报道。考虑到进入临床试验治疗肺动脉高压的伊马替尼,PDGF受体抑制剂,第一个专利是致力于酪氨酸激酶受体抑制剂,如PDGFR和c - kit。随后,除了激酶受体,其他途径参与了肺动脉高压的作用已经出现并且一些研究小组集中把他们的注意力集中在非受体激酶上。关于这一主题的15个专利报道新的目标和新的衍生品。然而,虽然肺动脉高压是可治疗疾病,大多名发明的化合物只服从抗增殖化验而不服从实验动物模型的特定测试。 结论:综述证实连续研究工作旨在确定新的目标和新的药物为治疗肺动脉高压。几种激酶的抑制剂被描述。这些化合物可以主要抑制重要分支流程和病理性血管的生长,从而可能增加病人的寿命。
关键词: 肺动脉高血压,治疗,激酶抑制剂,专利,杂环化合物。
Current Medicinal Chemistry
Title:Small-Molecules Targeting Kinases Involved in Pulmonary Hypertension: a Patent Review (2010-2015)
Volume: 23 Issue: 30
Author(s): Rita Morigi, Mirella Rambaldi, Alessandra Locatelli, Alberto Leoni
Affiliation:
关键词: 肺动脉高血压,治疗,激酶抑制剂,专利,杂环化合物。
摘要: Background: Despite the fact that in recent years, a substantial progress has been made in the treatment of pulmonary hypertension, it is still a severe disease characterized by poor prognosis, and the search for new drugs remains a priority. Current remedies address mainly the vasoconstrictor/ vasodilator imbalance in the pulmonary circulation, while the causes of the disease are only moderately affected. Recently, the role of receptor and non receptor kinases in pulmonary hypertension has emerged and these targets were extensively considered for the development of new therapeutic strategies. This review discusses the patents on small-molecules targeting kinases involved in the proliferation/apoptosis imbalance, typically present in pulmonary hypertension.
Methods: Bibliographic research for the inventions was carried out using Espacenet and Sci-Finder databases, “pulmonary hypertension and kinases” as research query and the range from 2010 to 2015. Only patents published in English were considered. A qualitative analysis of the contents of each patent was made to examine the reported compounds, the studies performed and the resulting conclusions.
Results: The review includes about thirty applications. Moreover, in order to illustrate the pathophisiology of the disease and the mechanisms of the targets, about forty additional papers were reported. Considering that imatinib, a PDGF receptor inhibitor, entered the clinical trials for the treatment of pulmonary hypertension, the first patents were devoted to inhibitors of tyrosine kinase receptors, such as PDGFR and c-Kit. Subsequently, in addition to kinase receptors, the role of other pathways involved in pulmonary hypertension has emerged, and some research groups have focused their attention also on non-receptor kinases. Fifteen patents on this topic reported these new targets and new derivatives. However, in most of the inventions, although the pulmonary hypertension is among the treatable diseases, the compounds were subjected only to antiproliferative assays and not to specific tests on animal models.
Conclusion: The studies reported in this review confirm the continuous research efforts aimed to identify new targets and new drugs for the treatment of pulmonary hypertension. Several inhibitors of kinase were described. These compounds could inhibit mainly important branching processes and pathological growth of blood vessels, thereby might increase the lifespan of patients.
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Rita Morigi, Mirella Rambaldi, Alessandra Locatelli, Alberto Leoni , Small-Molecules Targeting Kinases Involved in Pulmonary Hypertension: a Patent Review (2010-2015), Current Medicinal Chemistry 2016; 23 (30) . https://dx.doi.org/10.2174/0929867323666160809093451
DOI https://dx.doi.org/10.2174/0929867323666160809093451 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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