Observational Pregnancy Safety Study of Women Exposed to Nifurtimox During Pregnancy to Describe the Risk of Pregnancy and Maternal Complications and Other Events of Interest on the Developing Fetus, Neonate, and Infant

This is an observational study in which data from women with Chagas disease who will take or have already taken nifurtimox during pregnancy and the impact on their babies are studied.
Chagas disease is an inflammatory, infectious disease caused by the parasite Trypanosoma cruzi. This parasite is mainly spread by insects called triatomine bug. If Chagas disease is left untreated, it can later cause e.g. serious heart and digestive problems.
Nifurtimox has been used for more than 50 years to treat Chagas disease in children and adults.
It is not recommended to be used during pregnancy as data from animal studies indicate that it may harm the baby. Currently, there are not enough data to know if this is also the case in humans.
In this study, researchers want to collect data on the safety of nifurtimox use in pregnant women. To do this, researchers will collect the following information:
* Birth defects (abnormal and problematic structures or functions, a child is born with)
* Pregnancy outcomes (like live birth, preterm birth, still birth/death of the unborn baby, miscarriage, or abortion)
* Certain health problems of the child up to 12 months of age
* Certain health problems of the women experienced during pregnancy The data will be collected from different sources including telephone calls with the women or their doctor, CRFs (case reprt forms) or from medical records The researchers will compare the proportion of children with birth defects, pregnancy outcomes or certain health problems of the child or the women during pregnancy with available data on these outcomes in the general population.
The study will run for approximately 10 years.

开始日期2024-12-31

申办/合作机构

Bayer AG

CTR20220156

/ Recruiting临床1期

硝呋莫司片在成年中枢神经系统肿瘤患者中评价耐受性、安全性、药代动力学及初步抗肿瘤活性的Ia期临床试验

主要目的评价硝呋莫司在经标准治疗后复发或疾病进展、或无标准治疗的成年高级别脑胶质瘤、髓母细胞瘤、脑转移瘤（包括但不限于肺癌脑转移、乳腺癌脑转移、黑色素瘤脑转移等）患者的耐受性、安全性，确定最大耐受剂量（MTD）和/或II期推荐剂量（RP2D）。次要目的 1) 评价硝呋莫司在成年中枢神经系统肿瘤患者中的初步药代动力学特征； 2) 评价硝呋莫司在成年中枢神经系统肿瘤患者中的初步有效性。探索性目的探索硝呋莫司在成年中枢神经系统肿瘤患者中的给药方案。

开始日期2023-02-23

申办/合作机构

恒泰久康（天津）医药科技有限公司

CTR20190136

/ Recruiting临床1期

硝呋莫司治疗儿童复发或难治性神经母细胞瘤患者的单臂、非随机化、开放、剂量递增、I期临床试验

主要目的评价硝呋莫司单药及联合环磷酰胺及拓扑替康治疗儿童复发或难治性神经母细胞瘤患者的安全性，确定最大耐受剂量及 II 期推荐剂量。次要目的 1) 评价硝呋莫司单药及联合用药的初步药代动力学特征； 2) 评价硝呋莫司联合用药治疗儿童复发或难治性神经母细胞瘤患者的缓解率。探索性目的探索硝呋莫司联合用药的最佳给药方案。

开始日期2021-10-20

申办/合作机构

恒泰久康（天津）医药科技有限公司

100 项与硝呋替莫相关的临床结果

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100 项与硝呋替莫相关的转化医学

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100 项与硝呋替莫相关的专利（医药）

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938

项与硝呋替莫相关的文献（医药）

2025-01-01·BIOORGANIC CHEMISTRY

Discovery of a new eugenol-benznidazole hybrid active against different evolutive stages of Trypanosoma cruzi

Article

作者: Nonato, Maria Cristina ; de Melo, Ígor Matheus ; Dos Santos, Elda Gonçalves ; da Silva, Viviana Aparecida ; Stoco, Patricia Hermes ; de Souza, Thiago Belarmino ; Mansur Pontes, Carime Lessa ; Camargo, Tamires Pereira ; Caldas, Ivo Santana ; de Menezes Vaidergorn, Miguel

Chagas disease (CD) is a life-threatening illness caused by the protozoan Trypanosoma cruzi and there are only two drugs currently available for pharmacotherapy of this neglected infection (benznidazole and nifurtimox). Their limited efficacy in chronic phase of the disease, problems of toxicity and the growing resistance by the protozoan are directly associated to high rates of drug discontinuation by the patients. In the context of the search for new trypanocidal drug candidates, our group has been working with the chemical manipulation of eugenol to obtain new agents active against T. cruzi and promising results have been achieved. In this work we designed molecular hybrids between eugenol and benznidazole (BZN) by performing a bioisosteric replacement between the nitroimidazole ring of BZN by the eugenol or analogues nucleus in nitrated or non-nitrated forms. The obtained compounds were initially evaluated against epimastigote stages of T. cruzi for selecting the most active ones. Three hybrids (8, 10 and 15) showed activity against this evolutive stage and the most promising was eugenol nitro derivative 8 (IC₅₀: 24.7 µM) that showed a similar potential than BZN (IC₅₀: 29.9 µM). Compounds 8, 10 and 15 were then evaluated against infective trypomastigote and intracellular amastigote forms of T. cruzi and the cytotoxicity of them was investigated against healthy Vero and H9c2 cells. The nitro derivative 8 was once again the most promising compound against trypomastigote (IC₅₀: 1.8 µM) and amastigote (IC₅₀: 1.6 µM) forms, with selectivity indices greater than 63 considering both health cells evaluated. This compound was more active than BZN, that showed IC₅₀ values of 6.1 µM (trypomastigotes) and 3.1 µM (amastigotes) and showed the most significant effect in reducing the infection rate and accumulation of parasites in infected cells. Calculated logP values suggest that the higher lipophilicity of derivative 8 (clogP: 3.25) in relation to BZN (clogP: 0.77) may be correlated to a greater ability of this eugenol derivative to cross the membranes of infected cells. Finally, to try understand the possible mode of action for compound 8, we have evaluated three important targets of the parasite (T. cruzi nitroreductase type I - TcNRT, trypanothione reductase - TR and mitochondrial membrane depolarization), but none of these metabolic pathways seem to be related to the mechanism of action of this compound. All in vitro assays employed the T. cruzi Y strain which exhibits partial resistance to benznidazole and these results indicate compound 8 as a new promising hit for the development of drug candidates to treat CD.

2024-12-01·Medicinal Chemistry

In vitro and In vivo Biological Activity of Two Aryloxy-naphthoquinones in Mice Infected with Trypanosoma cruzi Strains

Article

作者: Vázquez, Karina ; Moreno-Rodríguez, Adriana ; Bocanegra-García, Virgilio ; Cervera, Yobana Pérez ; Salas, Cristian O. ; Bertrand, Jeanluc ; Rivera, Gildardo ; Domínguez-Díaz, Luis R.

Background::

Chagas disease, a condition caused by Trypanosoma cruzi, is an endemic disease in Latin American countries that affects approximately eight million people worldwide. It is a continuing public health problem. As nifurtimox and benznidazole are the two pharmacological treatments currently used to treat it, the present research proposes new therapeutic alternatives. Previous studies conducted on naphthoquinone derivatives have found interesting trypanocidal effects on epimastigotes, with the molecules 2-phenoxy-1,4-naphthoquinone (IC50= 50 nM and SI < 250) and 2-(3-nitrophenoxy)-naphthalene-1,4-dione (IC50= 20 nM and SI=625) presenting the best biological activity.

Methods::

The present study evaluated the efficacy of in vitro, ex vivo and in vivo models of two aryloxyquinones, 2-phenoxy-1,4-naphthoquinone (1) and 2-(3-nitrophenoxy)-naphthalene-1,4- dione (2), against two Mexican T. cruzi strains in both their epimastigote and blood Trypomastigote stage. Both compounds were evaluated against T. cruzi using a mouse model (CD1) infected with Mexican isolates of T. cruzi, nifurtimox and benznidazole used as control drugs. Finally, the cytotoxicity of the two compounds against the J774.2 mouse macrophage cell line was also determined.

Results::

The in vitro and in vivo results obtained indicated that both quinones were more active than the reference drugs. Compound 1 presents in vivo activity, showing up to 40% parasite reduction after 8 h of administration, a finding which is 1.25 times more effective than the results obtained using nifurtimox.

Conclusion::

These are encouraging results for proposing new naphthoquinone derivatives with potential anti-T. cruzi activity.

2024-11-21·Journal of biomolecular structure & dynamics

The Amaryllidaceae alkaloid, montanine, is a potential inhibitor of the Trypanosoma cruzi trans-sialidase enzyme

Article

作者: Manu, Prince ; Mensah, Jehoshaphat Oppong ; Borquaye, Lawrence Sheringham ; Gasu, Edward Ntim

Trypanosoma cruzi is the parasite that causes the chronic malady known as Chagas disease (CD). Only nifurtimox and benznidazole are currently approved to treat CD in acute and chronic phases. To minimize the danger of disease transmission and as a therapy, new compounds that are safer and more effective are required. It has been demonstrated that Amaryllidaceae plants suppress the growth of T. cruzi - the causative agent of CD. However, little research has been done on their potential protein targets in the parasite. In this study, an in-silico approach was used to investigate the interactions of the Amaryllidaceae alkaloids with trans-sialidase, a confirmed protein target of T. cruzi. The nature and efficiency of the main binding modes of the alkaloids were investigated by molecular docking. Trans-sialidase active site residues were bound by the alkaloids with binding energies varying from -8.9 to -6.9 kcal/mol. From the molecular docking investigation, all the alkaloids had strong interactions with the crucial amino acid residues (Glu230, Tyr342, and Asp59) required for trans-sialidase catalysis. Montanine was the most stable compound throughout the molecular dynamics simulation and had a favorable docking binding energy (-8.9 kcal/mol). The binding free energy (MM-GBSA) of the montanine complex was -14.6 kcal/mol. The pharmacokinetic properties investigated demonstrated that all the evaluated compounds exhibit suitable oral administration requirements. Overall, this in silico study suggests that the Amaryllidaceae alkaloids could potentially act as inhibitors of trans-sialidase.Communicated by Ramaswamy H. Sarma.

项与硝呋替莫相关的新闻（医药）

2024-12-21

·漫游药化

FDA批准上市的38个小分子药物结构

FDA今年很忙，但是再忙也未敢忘批药，截至2021年1月1日，FDA批准了53款新药，其中有38个小分子药物，作为化学人一定会很好奇这些化合物有啥特点，结构是啥，小编今天就带大家先睹为快。 1，Avapritinib (BLU-285) 阿伐普利尼 Avapritinib (BLU-285)是一种小分子激酶抑制剂，可有效抑制PDGFRα D842V突变体的活性、在细胞背景下抑制PDGFRα D842V自我磷酸化（IC50=30 nM）；同时也是KIT突变（KIT D816V）的抑制剂（IC50=0.5 nM）。 2，Tazemetostat (EPZ-6438) Tazverik(tazemetostat) (EPZ-6438) 是组蛋白赖氨酸甲基转移酶（Histone-Lysine N-methyltransferase）EZH2的抑制剂。 3，Pizensy(乳糖醇) Pizensy是一种口服的乳果糖类似物。它是一种渗透性泻药（osmotic laxitaive），可促进水分流入肠道，进而在结肠内达到通便作用。 4，Nexletol (bempedoic acid) bempedoic acid由美国Esperion Therapeutic 公司研发，是一种治疗血脂异常及降低其他心血管疾病风险的新型小分子化合物。合成路线如下： 5，Barhemsys(氨磺必利) 氨磺必利是一个多巴胺D2和D3受体阻断剂，上世纪80年代开始应用于精神分裂症治疗。 6，Nurtec ODT（rimegepant） Biohaven公司的口服CGRP抑制剂rimegepant，用于成人偏头痛的急性治疗。 7， Isturisa(osilodrostat) 3月6日，FDA批准库欣综合征（Cushing syndrome，CS）一线用药Osilodrostat上市，商品名：Isturisa，患者无论是否接受受过垂体切除手术治疗，都可应用Osilodrostat作为治疗药物。Osilodrostat是FDA批准的首个11-β羟化酶抑制，可直接阻断肾上腺皮质醇合成。 8，Zeposia(ozanimod) ozanimod（商品名ZEPOSIA），用于成人复发性MS（RRMS）患者的治疗。 9，Selumetinib（司美替尼） Selumetinib （司美替尼）（ARRY-142886 ; AZD6244）是一种MEK 1/2抑制剂和潜在的新药，由AlstraZeneca于2003年获得Array BioPharma Inc.的许可。阿斯利康和MSD于2017年签订了selumetinib的共同开发和联合商业化协议。 10，Tukysa(Tucatinib) Tukysa（Tucatinib）妥卡替尼 /图卡替尼 (ONT-380)是一种口服TKI(酪氨酸激酶)抑制剂，对HER2具有高度特异性，但对同属人表皮生长因子受体家族的EGFR没有明显抑制作用。 11，Pemigatinib （帕米加替尼） Pemigatinib（INCB054828）是一种口服有效的，选择性FGFR抑制剂，它对FGFR1，FGFR2，FGFR3，FGFR4的IC50值分别为0.4 nM，0.5 nM，1.2 nM和30 nM。 12，Ongentys(opicapone) 13，INCB28060 (Capmatinib) 卡马替尼；苯扎米特 INCB28060是一种新型， ATP竞争性的c-MET抑制剂，IC50为0.13 nM，抑制RONβ， EGFR和HER-3活性。 14，Selpercatinib (LOXO-292) 塞尔帕替尼 Selpercatinib（LOXO-292）是一种有效的，特异性RET抑制剂。 15，Ripretinib 瑞普替尼 Ripretinib（DCC-2618）是一种具有口服活性的，选择性的KIT和PDGFR-alpha抑制剂。 16， Cerianna (fluoroestradiol F18) 17，Artesunate（青蒿琥酯）青蒿琥酯是一类控制疟疾症状的抗疟药。 18，Tauvid（flortaucipir F18） Tauvid（flortaucipir F18）是第一种获得FDA批准，帮助对大脑中的tau病理进行成像的药物。Tauvid是一种放射性诊断试剂，用于需要接受阿尔茨海默病评估的认知障碍成人患者。 19，Lurbinectedin（卢比克替定） lurbinectedin是PharmaMar研发的海鞘素衍生物，为肿瘤创新药。目前，绿叶制药与PharmaMar在华合作共同开发该药物。 20，Dojolvi（triheptanoin）三庚酸甘油酯 Dojolvi（triheptanoin）三庚酸甘油酯，是一种高纯度、人工合成的7碳脂肪酸甘油三酯，在甘油骨架上通过多个化学合成步骤添加了三个7碳脂肪酸形成。专门为LC-FAOD患者提供中链、奇数碳脂肪酸作为能源和代谢产物替代品。 21，Fostemsavir(BMS-663068) Fostemsavir (BMS-663068) 是 BMS-626529 的原药，能结合gp120，抑制 HIV-1 与细胞 CD4 受体的结合。 22，Byfavo（Remimazolam）瑞米唑仑/雷米马唑仑 Byfavo（Remimazolam）瑞米唑仑/雷米马唑仑是一种起效和失效迅速的静脉注射苯二氮卓（benzodiazepine）镇静剂。可用于在时长不超过30分钟的有创医疗程序中，例如结肠镜检查和支气管镜检查。 23，Inqovi(cedazuridine+地西他滨) Inqovi（cedazuridine/decitabine[地西他滨]，口服C-DEC，ASTX727），该药用于骨髓增生异常综合症（MDS）和慢性骨髓单核细胞白血病（CMML）成人患者的治疗。 24，Xeglyze(Abametapir) Xeglyze（Abametapir）0.74％洗护剂是一种金属蛋白酶抑制剂，金属蛋白酶是对虫卵发育和若虫和成虫虱子存活，至关重要的生理过程所必需的酶。 25，Nifurtimox (Synonyms: 硝呋替莫) Nifurtimox 是一种用于锥虫病 (Trypanosoma cruzi) 的抗虫剂。Nifurtimox 有潜力用于神经母细胞瘤细胞的研究。Nifurtimox 影响乳酸脱氢酶 (LDH) 活性。 26，Olinvyk（oliceridine） Olinvyk的活性药物成分为oliceridine，这是一种首创的（first-in-class）静脉镇痛药。oliceridine是首个G蛋白选择性激动剂，与静脉注射吗啡相比，镇痛效果更好。oliceridine以μ阿片受体为靶点，通过一种优化作用机制（MOA），优先参与负责疗效的信号通路，减少引起不良反应的信号通路的激活。 27， Evrysdi(risdiplam) risdiplam是治疗所有3种类型SMA的首个口服药物。 28，Winlevi(clascoterone) Clascoterone（又称CB-03-01）是一种局部雄激素受体（AR）抑制剂，该新的化学实体正在开发治疗痤疮（暂定品牌名为Winlevi）和男女性脱发（暂定品牌名Breezula）。根据美国FDA审查其1%浓度治疗痤疮以及后期开发其高浓度溶液治疗男性雄激素雄性脱发的结果，其被认为是一种“first-in-class”药物。值得一提的是，这是近40年来针对痤疮治疗的首个新机制药物。 29，Detectnet（Cu 64 DOTATATE）放射性诊断试剂铜64盐酸盐 Detectnet是首款将Cu 64放射性同位素与生长抑素类似物DOTATATE偶联的诊断试剂。 30，Pralsetinib 普雷西替尼 Pralsetinib (Blu-667) 是新一代的，高效的，选择性RET抑制剂，对于WT RET，RET突变体V804L，V804M，M918T和CCDC6-RET的IC50为0.3-0.4 nM。 31，瑞德西韦（Remdesivir） 2020年10月22日，美国食品药品管理局（FDA）批准了吉利德科学的抗病毒药物瑞德西韦用于治疗新冠住院患者，成为美国首个正式获批的新冠治疗药物。 32，Lonafarnib (Synonyms: Sch66336) Lonafarnib 是一种口服有效的法尼基蛋白转移酶 (FPTase) 抑制剂，作用于 H-ras，K-ras 和 N-ras，IC50 分别为 1.9 nM，5.2 nM 和 2.8 nM。Lonafarnib 具有抗肝炎三角洲病毒 (HDV) 的活性。 33， Imcivree(Setmelanotide) setmelanotide是一款首创、寡肽类MC4R激动剂，开发用于治疗罕见肥胖遗传性疾病。 34，Gallium 68 PSMA-11 35，Orladeyo（Berotralstat）贝罗司他 rladeyo（Berotralstat）贝罗司他是一种新型、口服、每日1次、强效、选择性人血浆激肽释放酶抑制剂，通过抑制激肽释放酶来阻止缓激肽的生成从而预防水肿发作。Orladeyo （berotralstat）用于预防12岁及以上儿童和成人遗传性血管性水肿（HAE）发作，Orladeyo是首个预防HAE发作的口服非甾体药物。 36，Tirbanibulin (Synonyms: KX2-391; KX-01) 37，Relugolix 瑞卢戈利 Relugolix，也称为TAK-385，是一种口服活性的黄体激素释放激素（LH-RH）受体拮抗剂，IC50为0.12 nM。 38,Gemtesa（vibegron） vibegron可治疗膀胱过度活动症导致的急迫性尿失禁，尿急和尿频等症状。

上市批准临床结果

2024-07-19

·精准药物

【J Med Chem】2013-2023 FDA批准药物含氮优势骨架

侃言所谓“无氮不成药”，虽然不是那么绝对，但含氮杂环或基团在药物成分中出现的频率一向居高。本周五，美国亚利桑那大学（就是那个经常统计每年最畅销药物的团队）统计了自2013至2023年间FDA批准的231款独特的小分子化合物，对它们的结构和性质进行分析，以及重要杂原子如硫、氟、和关键小氮取代基（CN、NO2）的频率信息，刊载在J Med Chem上。 https://doi.org/10.1021/acs.jmedchem.4c01122 相比于上一次1938-2012年的统计（下图一），本次统计（下图二）发生了很大的重新洗牌！接下来一起看看详细内容。图一：1938-2012年FDA批准药物高频含氮骨架图二：2013-2023年FDA批准药物高频含氮骨架 01 分析总览本次分析了2013年1月至2023年12月共11年间批准的药物，其中包含321种独特的小分子药物，包括36种（约11%）是联合用药的新型结构。与2014年的统计分析相比，含氮杂环的药物产生了惊人的增长，先前的研究显示59%的药物含有至少一个氮杂环，而本次统计分析显示82%的新批准的小分子药物含有氮杂环。此外，每个药物的氮杂环数量也显著增加，33%的药物含有2个氮杂环，23%的药物含有3个氮杂环，8%的药物含有4个氮杂环；而还有2款批准药物结构中还有6个氮杂环！不同类型的氮杂环出来频率表出显著的增长，其中大多数在早期的研究中（2014年）并不存在。六元非芳香族氮杂环最为常见，其次是融合型和六元芳香性氮杂环，如下图。毫不奇怪，这些氮杂环中的大多数是由六元或五元芳香族环或非芳香族环组成的，在此之外，含氮大环则是最大的一类。而且，经典的天然产物衍生的氮杂环化合物，如阿西芬、戊南、吗啡、萜类生物碱和麦角碱，在这个数据集中几乎没有出现。除了碳、氢、氧、氮以外的元素，还分析了更多的元素出现频率，如上图，其中氟、硫、氯是这些原子取代中最重要的代表。统计中显示，34%的药物中至少含有一个氟取代基，23%药物中含有硫取代基，17%的药物中含有至少一个氯取代原子。在这些批准药物中，最大的一组被批准用于癌症治疗，包含89种（28%），其中55种是激酶抑制剂。抗感染药物是第二常见的疾病类别，有56种（17%）新药，其中10种被批准用于丙型肝炎。这些新的丙型肝炎药物因其复杂性、立体化学丰富性、对称性的使用、取代基的多样性以及不常见的喹诺啉氮杂环和阿吡咯烷以及在许多情况下含氮大环的使用而更加引人注目。这些药物中还包括5种偏头痛、6种新型糖尿病小分子药物，以及帕金森病、多发性硬化症、阿尔兹海默病等的新型药物。而针对眼部、皮肤、肠道相关疾病的多种新型小分子治疗方式也在过去的十年间出现。如上图，按照在FDA批准药物小分子中出现的频率，排名前35的氮杂环。每个方框中以彩色标记氮杂环，#号为其出现频率排名，灰色条形图按比例绘制，代表该氮杂环骨架出现在多少药物分子中。此次35种氮杂环排名与先前2014年统计的25种氮杂环排名，出现了许多新型的结构，Top排名也发生了大洗牌！在前5最常见的氮杂环中，吡啶取代了哌啶，跃居首位，哌啶退居第2，吡咯烷由第5升至第3，哌嗪从第3降至第4，嘧啶从原先的第10上升至第5。 02 含氮优势骨架 # 1 吡啶吡啶是最常见的氮杂环，取代了之前分析中排名第一的哌啶。共54种含吡啶的药物，如下图。 #2 哌啶在过去的11年里，总共有40种含哌啶的药物被批准。哌啶类药物包括一种内酰胺(ubrogeogen)和两种戊二胺(gepirone和泊马度胺)。大多数哌啶类药物在1-(81%)或4位(72%)或两者都含有取代基(40%)。一半的哌啶是双取代的，其次是三取代(23%)和单取代(14%)。这些哌啶类药物中有13种(33%)是非手性的，并且总共有16种(40%)哌啶类核心含有至少一个手性碳原子。大多数哌啶类药物被批准用于治疗癌症。 # 3 吡咯烷在这个数据集中总共出现了40种含吡咯烷的药物。 # 4 哌嗪哌嗪类药物是该数据集中第四个最常见的氮杂环，以36种独特的新小分子药物为代表。 # 5 嘧啶嘧啶类药物排名第五，共有25个新小分子药物成员。 # 6 吡唑吡唑类是氮杂环化合物中排名爬升最高的！在最初的美国FDA药物分析中没有出现在前25名中，而在过去的11年里，共有20种独特的小分子药物出现！ # 7 吲哚共有21种小分子吲哚药物和诊断方法获得批准。 # 8 咪唑共有18种咪唑药物。 # 9 吗啉共有13种吗啉药物。 # 10 苯并咪唑共有10种苯并咪唑药物。 # 11 1,2,3/4-三氮唑共有9种1,2,3/4-三氮唑药物。 # 12 噻唑共有8种噻唑药物。 # 13 尿嘧啶共有7种尿嘧啶药物。 # 14 吡啶酮共有6种吡啶酮药物。 # 15 四氢异喹啉共有6种四氢异喹啉药物。 # 16 喹啉共有6种喹啉药物。 # 17 喹唑啉共有5种喹唑啉药物。 # 18 吡咯并嘧啶，#19 吡唑并嘧啶， #20吡咯并嘧啶 # 21 嘌呤， # 22 吲唑， # 23 吡咯酮 # 24 1,3-噁嗪烷， #25 苯并吡嗪， # 26 氮杂环丁烷 # 27 喹啉酮，#28 异喹啉酮， # 29 四氮唑， #30 异恶唑 # 31 氮杂双环酮，#32 吡唑并吡啶 # 33 氮杂环庚烷，#34 吡咯并三唑 # 35 噻二唑大环多胺 03 频繁出现的官能团和原子重要的小氮取代基：腈和硝基在过去的11年里，有22种新的含腈药物被批准，其中一半被批准用于治疗癌症，5种被批准用于治疗病毒和真菌感染。结构上最有趣和最活跃或最不稳定的腈基团可能是那些在共轭腈和核苷腈中发现的。该数据集中出现了8种新的含硝基药物，其中一半是咪唑环的取代基和硝基咪唑抗生素的成员。其中两种硝基药物(苯并硝唑和硝呋替莫)已被批准用于治疗Chagas病。含氟药物小分子氟在新批准的杂原子取代小分子药物中占主导地位，有107个（34%）。其中，最频繁的是单氟取代芳基/杂芳基取代基，其次是三氟甲基取代芳基/杂芳基、三氟甲基非芳香族取代、二氟甲基等。其它卤素：Cl、Br、I 含硫小分子药物含磷、氘代、硅、硼药物 04 理化性质分析如上图，对比两个时期FDA批准药物，可以看出在理化性质上有一个清晰的趋势，更多超越经验规则的药物批准上市。以Ro5规则为标准，2013年以前有10%的药物不符合Ro5经验规则；而这个比例在最近的11年间上升到了29%！以AbbVie的Tier规则利用计算机对理化性质进行更细致的分析，其中Tier 1是最有利的，Tier 7是最不利的，中间分7个层级。可以从上图底部的对比中看出，2013年以前的药物具有更有利的特征分布，其中超过50%的药物处于前三个层级；而2013年后的11年间，前三个层级仅超过25%，将近有一半的药物处于最不利的第7层级。这些变化，表明近些年药物开发组合的重大转变！在20世纪90年代以前，以神经递质胺类相关的GPCR靶点药物开发为主导；而当前以激酶抑制剂等靶点的药物开发占主导。在过去的20多年间，共有80多种激酶药物获批，其中58种是过去10年间获批的。而激酶类药物通常处于Ro5理化性质空间的尖端，66%的药物至少有一个违背Ro5，21%的药物有一个以上违背Ro5。相比之下，以神经递质胺类物质相关的GPCR药物通常满足Ro5，甚至在很多情况下通过Ro4、Ro3。如下是对平均分子量、平均AlogP对比的近些年的分析可视化散点图分布。很明显，与前几十年相比，过去十年中药物的分子量发生了重大变化；然而，药物的亲脂性几乎没有显著的变化。如下图，从两组药物性质的分布可以看出这一点，在分子量中差异有统计学意义(α值=0.05)，而在Alogp中差异无统计学意义。药物转向更具挑战性、不易分解的化学物质的另一个迹象是整体化合物质量的下降。化合物质量可通过QED、PFI、AB-MPS等药物相似性指标进行量化。在所有情况下，这些的平均值都朝着表明质量较差的方向移动,如下图和表。这一趋势在APT分布中也很明显，2013年之前的药物具有更有利的物理化学层的化合物。从下图平均QED与平均AB-MPS的对比图更进一步说明药物质量的变化。随着时间的推移，药物性质的另一个显著变化是总体拓扑极性表面积(TPSA)的显著上升，这表明药物随着尺寸的增加而变得更加极性。这种TPSA的增加并不完全是分子量增加的结果，因为与2013年之前相比，过去十年中每重原子的TPSA也有显著差异，如下图。这一增长很可能是由于药物中氮和氧原子百分比的上升，与前几十年相比，过去十年中氮和氧原子的比例明显增加了约17%。如下图的饼图，是最近11年药物Ro5比例分布的逐年变化趋势。从其它分析化合物的参数对比来看，逐年变化如下图。总结这项分析对过去11年FDA批准小分子药物进行了具体的刨析和总结，一方面对含氮杂环和基团进行了分类、统计、和分析，另一方面，也对氮以外的氟、硫、氯、溴、碘、磷、氘、硼、硅等元素进行了总结。如上图。关于氮杂环的代表性，变化最为显著，新批准的含氮杂环的药物从早期数据集的59%增加到82%，并且主要转向含多个氮杂环的药物。许多排名靠前的氮杂环是相同的，但随着许多新成员的加入，排名也发生了变化。该数据集中药物结构的多样性，它们的复杂性，以及新原子和官能团的包含确实令人印象深刻和鼓舞人心。与之前的几十年相比，化学复杂性的增加导致了过去11年中药物的分子量大小的增加，以及批准的超过Ro5的药物数量的增加。显然，为了患者的利益而追求高价值的药物靶点人类动用了一切可以动用的手段，并打破常规，尝试一切可能！声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

上市批准医药出海

2024-04-16

·PRNewswire

Health Alert: Chagas Disease, Also Known as American Trypanosomiasis, Poses Life-Threatening Risk from Trypanosoma Cruzi Parasite: BCC Research LLC

Chagas disease, which is also known as American trypanosomiasis, occurs when you get infected with a small parasite called Trypanosoma cruzi. A doctor named Carlos RJ Chagas from Brazil discovered this parasite and how it causes illness in people way back in 1909. BOSTON, April 16, 2024 /PRNewswire/ -- The new research gives a complete picture of the Chagas Disease: American trypanosomiasis market. It looks at trends in the CD market, including how common it is in different regions, and talks about what's happening in the market right now. The report also looks closely at the competition between different treatments. It focuses on treatments available across Latin America. Because many people with Chagas Disease don't have enough money to buy medicine, there isn't much demand for these products. That's why pharmaceutical companies aren't putting a lot of effort into creating new treatments for Chagas disease now. Key Facts to Know About Chagas Disease: A Quick Overview About 6-7 million people, mostly in Latin America, have a bug bite disease called Chagas disease. It can be passed on by bugs, eating unsafe food, getting blood or organs from infected people, passing it from mother to baby, or accidents in labs. If treated early, Chagas disease caused by Trypanosoma cruzi can be cured. Treatment can also help stop the disease from getting worse and prevent passing it from mother to baby. Some people with long-term Chagas disease might have heart problems, and others might have stomach or brain issues. They might need special treatment for these. Ways to stop Chagas disease include controlling bugs in Latin America, checking blood before giv ing it to someone, and testing and treating girls, women who can have babies, newborns, and brothers and sisters of infected moms who haven't had treatment before. The Transmission of Chagas Disease in the American Market: Key Insights In Latin America, Chagas disease mostly spreads from poop or pee of blood-sucking bugs called kissing bugs. These bugs hide in cracks in houses and come out at night to feed on blood. When they bite, they often do it on the face. If someone scratches the bite and gets the poop or pee in their body, they can get infected with the parasite. T. cruzi can also be transmitted by: If you eat or drink something with T. cruzi in it, like food or drinks with poop or pee from infected bugs or opossums, you can get sick. This often causes outbreaks where people get very sick, and some even die. When a mom who has Chagas disease gives birth, she can pass it on to her baby. Getting blood or something made from blood from someone who has Chagas disease can also give you the disease. Signs and symptoms Chagas disease has two phases. In the first phase, which lasts about 2 months, a lot of parasites are in the blood, but most people don't have any symptoms or just feel a little unwell. Sometimes, people might see a spot on their skin or swelling around one eye. They could also have fever, headache, swollen glands, pale skin, muscle pain, trouble breathing, or pain in the belly or chest. In the second phase, the parasites hide in the heart and stomach muscles. After one to three decades, about a third of patients have heart problems, and about one in ten have stomach issues. Over time, the infection can damage the nerves and heart muscles, causing heart problems, irregular heartbeats, heart failure, or sudden death. Chagas Disease Treatment in the American Market Chagas disease can be treated with medicines like benznidazole or nifurtimox to kill the parasite. These drugs work best if given early, especially during the first phase of the disease. Treatment can also help prevent the disease from getting worse. However, treatment can have side effects, and it's not recommended for pregnant women or people with certain health conditions. In some cases, additional treatment may be needed for heart, digestive, or nerve problems caused by the disease. Control and Prevention In different places, the World Health Organization WHO (World Health Organisation) suggests various ways to prevent and control Chagas disease: Using bug sprays inside homes and nearby areas to kill insects and keep them away. Fixing up homes and keeping them clean to stop bugs from getting in. Using bed nets and practicing good hygiene when handling food, during transport, and storage to prevent infection. Creating easy-to-understand information and education programs for different situations and people about how to prevent the disease and use surveillance tools. Checking blood donors to make sure they don't have the disease. Checking organ, tissue, or cell donors and recipients to make sure they don't have the disease Here are the top 5 key companies in the Chagas Disease (American trypanosomiasis) market along with brief descriptions: Bayer AG: A multinational pharmaceutical company known for its commitment to global health initiatives, including research and development of treatments for neglected tropical diseases like Chagas Disease. Sanofi S.A.: A leading pharmaceutical company with a focus on innovative treatments for various diseases, including neglected tropical diseases such as Chagas Disease. GlaxoSmithKline plc: A global healthcare company dedicated to developing vaccines and treatments for infectious diseases, including Chagas Disease. Novartis AG: A pharmaceutical company known for its research and development efforts in addressing unmet medical needs, including the development of therapies for neglected tropical diseases like Chagas Disease. Merck & Co., Inc.: A leading global healthcare company committed to developing innovative treatments and vaccines for a wide range of diseases, including Chagas Disease. Directly Purchase a copy of the report with BCC Research. For further information or to make a purchase, please get in touch with [email protected]. About BCC Research BCC Research provides objective, unbiased measurement and assessment of market opportunities with detailed market research reports. Our experienced industry analysts' goal is to help you make informed business decisions, free of noise and hype. Contact Us Corporate HQ: 50 Milk St. Ste 16, Boston, MA 02109, USA Email: [email protected], Phone: +1 781-489-7301 For media inquiries, email [email protected] or visit our media page for access to our market research library. Data and analysis extracted from this press release must be accompanied by a statement identifying BCC Research LLC as the source and publisher. Logo: SOURCE BCC Research LLC

疫苗

100 项与硝呋替莫相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00833	硝呋替莫	P01CC01	DB11820

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
Chagas病	美国	Bayer HealthCare Pharmaceuticals, Inc.	2020-08-06

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
髓母细胞瘤	临床2期	美国	Bayer AG	2008-01-14
复发性神经母细胞瘤	临床2期	美国	Bayer AG	2008-01-14
神经母细胞瘤	临床1期	中国	恒泰久康（天津）医药科技有限公司	2021-10-20
Chagas心肌病	临床1期	阿根廷	Bayer AG	2013-11-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


CHICO SECURE (Pubmed \| Antimicrob Agents Chemother)	N/A	Chagas病	-	Nifurtimox 60-day regimen	選餘淵觸餘選鹽網鹽獵(願淵鑰壓遞鏇繭築遞願) = No adverse events potentially related to treatment or caused by protocol-required procedures were documented for either treatment regimen 範繭襯構窪廠夢襯窪齋 (鹹顧餘糧鑰繭鑰憲積衊 ) 更多	-	2023-03-28
				Nifurtimox 30-day regimen
NCT00601003 (CTgov)	临床2期	复发性神经母细胞瘤 \| 髓母细胞瘤	112	Cyclophosphamide+Topotecan+Nifurtimox	鏇鑰壓範艱積蓋選願壓(膚築積醖憲襯襯鏇獵製) = 夢憲壓餘齋範願夢鹽鏇壓憲廠築醖廠艱製鬱範 (壓襯鹽齋鏇襯製糧餘衊, 襯鬱膚網顧鬱獵繭觸憲 ~ 廠願鹹廠築壓願艱蓋鹹) 更多	-	2022-12-29
NCT03784391 (Pubmed \| PLoS Negl Trop Dis)	N/A	Chagas病	3,000	Nifurtimox	蓋鬱遞獵繭顧糧積醖鹽(餘齋範窪壓淵壓鬱襯構) = 顧簾鑰選觸鬱鹽餘蓋遞顧願繭壓築鏇憲網鬱壓 (齋築廠積製構鏇構願願, 1.0 ~ 4.5) 更多	-	2021-10-01
				nifurtimox (No antitrypanosomal treatment)	蓋鬱遞獵繭顧糧積醖鹽(餘齋範窪壓淵壓鬱襯構) = 鏇壓廠鹽築鬱選顧製齋顧願繭壓築鏇憲網鬱壓 (齋築廠積製構鏇構願願, 1.0 ~ 4.2)
NCT02625974 (CHICO, Pubmed \| PLoS Negl Trop Dis) 人工标引	临床3期	Chagas病	330	Nifurtimox	選膚窪齋餘觸觸築廠壓(繭齋艱網鏇憲壓糧襯鑰): difference = 14.0 (95% CI, 3.7 ~ 24.2)	积极	2021-01-07
				placebo