A Phase 1, Single-dose, Non-Randomized, Open-label, Parallel-group Study to Assess the Pharmacokinetics and Safety of Lenabasum in Subjects with Hepatic Impairment Compared with Matched Healthy Controls

开始日期2020-07-27

申办/合作机构

Corbus Pharmaceuticals Holdings, Inc.

[+1]

100 项与 Ajulemic acid 相关的临床结果

登录后查看更多信息

100 项与 Ajulemic acid 相关的转化医学

登录后查看更多信息

100 项与 Ajulemic acid 相关的专利（医药）

登录后查看更多信息

127

项与 Ajulemic acid 相关的文献（医药）

2025-01-01·JID Innovations

Long-Term Safety and Efficacy of Lenabasum, a Cannabinoid Receptor Type 2 Agonist, in Patients with Dermatomyositis with Refractory Skin Disease: Follow-Up Data from a 3-Year Open-Label Extension Study

Article

作者: Werth, Victoria P. ; Poroye, Joy ; Werth, Victoria P ; Stone, Caroline J. ; Stone, Caroline J ; Lopes Almeida Gomes, Lais ; Xie, Lillian ; Ahuja, Geeta ; White, Barbara ; Faden, Daniella Forman ; Feng, Rui

Dermatomyositis (DM) is a rare autoimmune condition involving skin manifestations often resistant to standard treatments such as immunosuppressants and antimalarials. Biopsies show elevated inflammatory cells such as CD4+ T cells, dendritic cells, and cytokines. Lenabasum, a selective cannabinoid receptor 2 agonist, has demonstrated significant benefits in treating autoimmune skin diseases.OBJECTIVESThis study utilizes data from the open-label extension (OLE) phase of the lenabasum phase 2 trial and additional post-OLE follow-up data. Key aims include evaluating the drug's long-term effectiveness and assessing disease manifestation recurrence.METHODSThe phase 2 lenabasum trial enrolled patients with treatment-resistant, skin-predominant DM. The OLE consisted of a 3-year period during which 20 patients were on the drug for the entire duration, with assessments every 8 weeks to evaluate drug safety and efficacy. Subsequently, a follow-up retrospective chart review was performed on patients who completed the OLE as well as on control subjects with DM who did not participate in the lenabasum trial.RESULTSBy week 68, patients exhibited reductions in Cutaneous Dermatomyositis Disease Area and Severity Index activity score (-21.8), Patient Skin Activity Visual Analog Scale (-3.0), and Skindex-29 (-28.0) from OLE baseline. After OLE, 58.3% maintained stable disease, significantly higher than controls (P = .035), with 41.7% not experiencing flares compared with 91.6% of controls. In addition, 50% of patients reported sustained pruritus improvement.CONCLUSIONSData from OLE and subsequent follow-up periods demonstrate lenabasum's efficacy in maintaining disease stability, reducing flares, and improving DM symptoms, suggesting that it is a promising option for patients with treatment-resistant skin-predominant DM.TRIAL REGISTRATIONThis study was registered at clinicaltrials.gov, with NCT02466243. Study registration was first submitted on June 2, 2015.

2023-12-01·Journal of Investigative Dermatology

Validation of Cutaneous Dermatomyositis Disease Area and Severity Index Activity Score and Other Efficacy Outcomes as Measures of Skin Disease in Dermatomyositis in the Lenabasum Phase 3 Trial

Article

作者: Kleitsch, Julianne ; Dan, Joshua ; Werth, Victoria P ; White, Barbara ; Pandya, Rachita

In the past decade, there have been six industry-sponsored phase 3 trials in adult patients with dermatomyositis (DM), primarily focusing on improving muscle weakness. However, skin disease is a cardinal manifestation of DM. This study evaluated the sensitivity of Cutaneous Dermatomyositis Disease Area and Severity Index Activity score, Cutaneous Dermatomyositis Activity Investigator Global Assessment, Total Improvement Score, and other outcome measures used in DM clinical trials to detect improvement in DM skin disease activity. Data analyzed from the lenabasum phase 3 trial in DM showed that improvement in Cutaneous Dermatomyositis Disease Area and Severity Index Activity score increased proportionately with the degree of patient- or physician-reported improvement in skin disease, consistently measuring improvement when clinically meaningful improvement was reported at weeks 16-52. In contrast, Cutaneous Dermatomyositis Activity Investigator Global Assessment measured little change from baseline with reported no improvement in skin disease but also a similar change from baseline with slight improvement. No Skindex-29+3 subscale performed well at reflecting increasing degrees of improvement in skin disease. Extramuscular Global Assessment and Total Improvement Score generally showed increasing levels of improvement as the degree of patient- and physician-reported improvement in skin disease increased, but these are composite measures and are not specific to improvement in DM skin disease. To measure clinically meaningful improvement in skin disease in a DM trial, Cutaneous Dermatomyositis Disease Area and Severity Index Activity score is the more sensitive outcome measure across time points.

2023-09-01·Arthritis & rheumatology (Hoboken, N.J.)

Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis.

Article

作者: Dgetluck, Nancy ; Litinsky, Irena ; Matucci-Cerinic, Marco ; Simms, Robert W ; Kuwana, Masataka ; Hummers, Laura ; Sandorfi, Nora ; Spiera, Robert ; Stevens, Wendy ; Hsu, Vivien ; Furst, Daniel E ; Jun, Jae-Bum ; Gordon, Jessica ; Constantine, Scott ; Denton, Christopher P ; Lee, Eun Bong ; Kafaja, Suzanne ; Dinh, Quinn ; Steen, Virginia ; Chung, Lorina ; Finzel, Stephanie ; Frech, Tracy M ; White, Barbara ; Leszcyzński, Piotr ; de Vries-Bouwstra, Jeska ; Jankowski, Tomasz ; Mayes, Maureen ; Bloom, Bradley J ; Khanna, Dinesh ; Levy, Yair ; Distler, Oliver

OBJECTIVEThis phase 3 study was undertaken to investigate the efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in patients with diffuse cutaneous systemic sclerosis (dcSSc).METHODSA multinational double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments, including immunosuppressive therapies (IST).RESULTSThe primary end point, the American College of Rheumatology combined response index in dcSSc (CRISS) at week 52 for lenabasum 20 mg twice a day versus placebo, was not met, with CRISS score of 0.888 versus 0.887 (P = 0.4972, using mixed models repeated measures [MMRM]). The change in the modified Rodnan skin thickness score (MRSS) at week 52 for lenabasum 20 mg twice a day versus placebo was -6.7 versus -8.1 (P = 0.1183, using MMRM). Prespecified analyses showed higher CRISS scores, greater improvement in MRSS, and lower decline in forced vital capacity in patients on background mycophenolate and those who were taking IST for ≤1 year. No deaths or excess in serious or severe adverse events related to lenabasum were observed.CONCLUSIONA benefit of lenabasum in dcSSc was not demonstrated. Most patients were treated with background IST, and treatment with mycophenolate mofetil in particular was associated with better outcomes. These findings support the use of IST in the treatment of dcSSc and highlight the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as to clinical care.

项与 Ajulemic acid 相关的新闻（医药）

2023-12-27

·智慧芽新药科讯

大麻和大麻素受体新药研发简报

关于大麻和大麻素受体历史上大麻是一种药品，由大麻属植物制成，其主要的成分为四氢大麻酚（Tetrahydrocannabinol, THC）和大麻二酚 (Cannabidiol，CBD)。大麻素是从大麻里发现的一组萜酚类化合物，也自然地存在于动物神经和免疫系统里。1980年代，人们发现了两种对大麻素有特异反应的 G 蛋白偶联受体，分别是大麻素受体 1（CB1）和大麻素受体 2（CB2）。大麻素受体和内源性大麻素不仅参与调节中枢和外周神经系统的许多生理功能，还参与调节人体许多外周部位的生理功能：内分泌系统、免疫系统、胃肠道、心血管系统和生殖系统。CB1 受体虽然主要存在于大脑，但在脾脏、肺、胸腺、心脏和血管中也有表达。在中枢神经系统中，它们在杏仁核、海马、皮层、基底节和小脑中神经元的轴突和突触前末梢的表达量最高。它们与 GABA 能（抑制性）和谷氨酸能（兴奋性）神经元密切相关，介导抑制性和兴奋性神经递质的持续释放。CB2 受体在脑外（如脾脏、扁桃体、骨髓、胰腺、外周血白细胞）和脑内（星形胶质细胞和小胶质细胞）具有免疫功能的组织中最为丰富。它们具有调节免疫细胞迁移和细胞因子释放的功能，还在心血管和呼吸系统、骨骼、胃肠道、肝脏和生殖系统中发挥作用。大麻素根据其来源可分为 3 类：内源性大麻素、植物性大麻素和合成大麻素。内源性大麻素是人体内产生的化学物质，与某些植物大麻素一样附着在相同的受体(CB1 和CB2）。内源性大麻素化学物质有助于维持健康身体的平衡与和谐。研究最为广泛的两种内源性大麻素，即 Anandamide 和 2-AG，以及负责内源性大麻素代谢的酶，构成了内源性大麻素系统。 Anandamide 和 2-AG 以及其他植物大麻素的分子靶标不仅仅是 CB1 和 CB2，还有 TRPR 和 GPR55。内源性大麻素的一个主要特点是其前体存在于脂膜中，可通过一到两个快速酶解步骤合成，并释放到细胞外空间。植物性大麻素是从大麻植物中发现和提取的化学物质。大麻植物含有 100 多种已知的植物大麻素，通常植物大麻素在雌株未播种的花蕾中含量最高。THC 和 CBD 是研究最广泛的植物大麻素。目前只有一种植物大麻素产品获得了美国 FDA 的批准，即 CBD 口服液，该产品被批准用于治疗与罕见癫痫相关的癫痫发作。非 FDA 批准的 "医用大麻 "没有科学定义，但一般认为它是一种含有大麻植物中植物大麻素的产品，旨在缓解疾病症状。合成大麻素是在实验室中模仿植物大麻素制成的化学物质。美国 FDA 批准了 3 种合成大麻素产品，这些产品模仿植物大麻素 THC。合成大麻素可能比大麻提取的四氢大麻酚更有效。美国 FDA 批准的合成四氢大麻酚制剂 Nabilone (大麻隆) 和 Dronabinol(屈大麻酚) 适用于治疗与癌症化疗有关的恶心和呕吐；Dronabinol还适用于治疗与艾滋病患者体重减轻有关的厌食症。大麻素受体配体从结构上可分为五大化学类：经典类、非经典类、氨基烷基吲哚类、二十烷类和类肽化合物。经典类包含二苯并呋喃衍生物，其中最著名的是Δ9-THC 和 HU-210，后者是Δ8-THC 的合成类似物。非经典类包括缺少吡喃环的Δ9-THC 双环和三环类似物，如 (-)-CP 55,940 等。氨基烷基吲哚类（以 (+)-WIN 55,212-2 为代表）和二十烷类（由内源性大麻素组成）的结构与经典和非经典大麻素受体激动剂截然不同，彼此也有区别。类肽化合物包括内源性 Hemopressin、其衍生物 RVD-Hpα 和 VD-Hpα 以及新型 Pep19 都被证明具有大麻素受体配体的功能。新药研发简报根据智慧芽新药情报库统计，全球靶向大麻素受体 ( CB1 和 CB2 ) 的药物研发管线合计 256 例，其中约 119 个 (46%) 管线处于非在研阶段，74 个 (29%) 管线处于临床前研究阶段。5 款药物已获批上市 (Cannabidiol/Dronabinol大麻二酚/四氢大麻酚和 Rimonabant) ，6款药物处于临床2/3期或3期研究阶段，23款药物处于临床2期。除开发具有亚型选择性的 CB1 或 CB2 治疗性药物外，部分药物研发工作聚焦开发非选择性的 CB1/CB2 药物分子以及 CB1/2 与 5-HT1A、NMDA 受体等的多特异性药物。靶向 CB1 和 CB2 受体的临床适应症及药物研发机会包括：神经系统疾病治疗（如神经痛、癫痫、帕金森病等）、代谢性疾病（如肥胖、2型糖尿病、非酒精性脂肪性肝炎等）、疼痛管理（疼痛和神经痛）、免疫系统调节（如类风湿性关节炎、炎症性肠病等）、抗癌治疗和药物成瘾和心理健康等。针对 CB1 和 CB2 受体的新型药物可能包括激动剂、拮抗剂、部分激动剂、偏向性激动剂、别构调控剂等，以更精确地调节大麻素系统的活性，减少副作用。Cannabidiol/Dronabinol（大麻二酚/四氢大麻酚）是由 GW Pharmaceuticals 公司原研开发的一款治疗入睡和睡眠障碍的药物，2022 年首次在德国获批上市。Cannabidiol 是一种存在于大麻中的活性大麻素，可从大麻或非大麻植物中提取，可用于治疗与 Lennox-Gastaut 综合征或 Dravet syndrome 综合征相关的癫痫发作，以及缓解中度至重度神经性疼痛或其他疼痛症状。尽管目前正在研究其确切的医学影响，Cannabidiol 已显示出镇痛、抗惊厥、肌肉松弛、抗焦虑、抗精神病的前景，并显示出神经保护、抗炎和抗氧化活性等。Dronabinol是一种合成的 Δ9-四氢大麻酚（Δ⁹-THC），通过对 CB1 和 CB2 受体产生微弱的部分激动活性来发挥其作用，从而产生众所周知的吸食大麻的效果，如增加食欲、减轻疼痛以及改变情绪和认知过程。它已被不同国家和地区被批准用于治疗艾滋病患者因体重减轻而引起的厌食症，以及治疗因癌症化疗而引起的恶心和呕吐，这些患者对常规止吐药治疗无效。GW Pharmaceuticals 建立了世界领先的大麻素科学平台，以开发深层次、创新性的早期和晚期大麻素候选产品管线，以及高度专业化的种植和制造技术。GW 也是全球率先开发出了世界上第一种从大麻植物中提取的处方药并实现了商业化。与未经 FDA 批准的 Cannabidiol 产品或大麻衍生产品不同，GW 获得监管机构批准的产品组合可确保所生产的每一种产品的安全性和疗效都经过临床试验的全面评估、独立的同行评审、监管机构的批准，并始终如一地进行生产，以确保达到最高质量标准。2021年，JAZZ 公司耗资72亿美元将 GW Pharmaceuticals 公司收入麾下。Rimonabant 是由 Sanofi-Aventis 公司原研开发、生产和销售的一种厌食抗肥胖药物。它是大麻素受体 CB1 的反向激动剂，其主要作用途径是降低食欲。Rimonabant 是全球首个获准使用的选择性 CB1 受体阻断剂，2006 年首次获批上市后已在包括欧盟、墨西哥和巴西在内的 38 个国家获得批准。但该药在美国 FDA 的上市申请被驳回，这一决定是因为它可能会增加自杀念头和抑郁情绪。早期的临床观察发现，大麻会刺激食欲，这表明内源性大麻素系统参与了能量平衡的控制。Rimonabant 是第一种上市的 CB1 受体拮抗剂，被开发为抗肥胖药，通过阻断中枢大麻素活性可能会减少食物摄入量。2005-2006年前后，Sanofi-Aventis 及临床研究团队分别在《柳叶刀》(2篇)和《新英格兰医学杂志》撰文，介绍了Rimonabant 对超重患者减轻体重和心血管风险因素的影响、超重血脂异常患者代谢风险因素的影响以及对超重或肥胖 2 型糖尿病患者的疗效和耐受性。结果表明，对于二甲双胍或磺脲类药物控制不佳的超重或肥胖 2 型糖尿病患者来说，20 mg/天的Rimonabant 与饮食和运动相结合，可以减轻体重，改善 HbA1c 以及一系列心血管和代谢风险因素，具有临床意义。然而，对所有已发表的随机对照试验进行的一项元分析 (meta-analysis) 结果表明，每天服用 20 mg 的Rimonabant会增加精神不良事件（抑郁性情绪障碍和焦虑）的风险。Rimonabant引起的不良事件明显多于安慰剂，严重不良事件是安慰剂的 1.4 倍。服用Rimonabant的患者因抑郁情绪障碍而中断治疗的可能性是服用安慰剂患者的 2.5 倍。美国 FDA 对四项主要试验以及未发表的试验进行了分析，发现服用Rimonabant（20 mg/天）比服用安慰剂更容易出现精神方面的不良反应。此外，据报道有两名服用Rimonabant的患者死于自杀。美国从未批准该药物用于治疗肥胖症。此后，欧洲监管当局取消了Rimonabant的上市许可。Taranabant 是一款由 Merck 公司原研开发的一款 CB 受体小分子类反向激动剂。据悉，Taranabant 对超重病人的临床3期研究数据表现出与Rimonabant 相似的减重效果，但由于潜在的副作用等原因，Merck 公司终止了对 Taranabant 的临床开发。此后，多项与CB1 拮抗剂相关的临床在研项目受此影响而宣告终止，包括阿斯利康、辉瑞、BMS、AbbVie 等跨国大药企。明知前路艰险，但依然有勇士无畏前行。INV-202 是一款由 Inversago Pharma 公司开发的一款 CB1 拮抗剂。前车之鉴，Inversago Pharma 公司开发的第二代 CB1 受体拮抗剂拮抗剂旨在降低分子对血脑屏障的通透效率，将药物分子限定在中枢神经系统之外的外周系统。根据23年更新的一份临床1b期研究报告，INV-202的耐受性良好，没有出现严重或严重的治疗突发不良事件；最常见的不良事件与已知的 CB1 受体阻断对胃肠道的影响有关。INV-202 显著降低了3.5公斤的平均体重，同时还显著降低了腰围和体重指数。今年8月诺和诺德公司和 Inversago Pharma 宣布，诺和诺德已同意在达到某些开发和商业里程碑的情况下，以最高 10.75 亿美元的现金收购 Inversago。另一位长期致力于 CB 受体系统药物开发的公司 Corbus Pharmaceuticals 公司宣布，公司正在致力于开发第二代 CB1 受体拮抗剂 CRB-913，该项目目前处于临床申报阶段。根据公司11月更新的临床前研究数据表明，CRB-913 进入大脑的比例很低，而减肥效果显著。临床前的减肥数据，如此振奋人心。加之近几年肥胖市场的大热，Corbus 公司对CB1 受体相关管线的调整思路非常明显。Ajulemic acid (Lenabasum) 是由美国 Corbus Pharmaceuticals 公司原研开发的另一款 CB2 受体激动剂和 IL-1β 抑制剂，目前处于临床3期阶段。早期的临床研究结果表明，Ajulemic acid 对慢性神经病理性疼痛患者有止痛作用，但没有临床相关的精神或身体副作用。目前，该药的正在围绕盘状红斑狼疮、皮肌炎、系统性硬皮病、囊性纤维化、系统性红斑狼疮等皮肤疾病进行临床研究。(但该项目在近期的公司管线汇报中并未提及。)CardiolRx (Cannabidiol) 是一款由 Cardiol Therapeutics 公司原研开发的一款 CB1/CB2 反向激动剂。在研临床适应症为心血管疾病、心包炎、心肌炎和心脏衰竭。CB1/CB2 新药开发策略尽管 CB1/CB2 具有广泛的治疗潜力，但候选药物的开发却受到不良反应、快速耐受性发展和滥用可能性的阻碍。有人提出，配体是否可通过产生偏向性信号转导，作为一种新药开发策略，将 CB1/CB2 受体的治疗效果和不良反应区分开来。但由于缺乏强偏性激动剂，人们对 CB1 受体的偏性信号转导了解甚少。研究人员对经典大麻素激动剂和异构配体的偏向信号转导特征进行调查研究，寻找 CB1 受体偏向信号转导在不同病理状态下的潜在治疗优势。CP55940 是一款由辉瑞公司 1974 年原研开发的一种合成大麻素。它可模拟天然四氢大麻酚的效果，作为 CB1/CB2 激动剂发挥作用。据报道，CP55940 的药效是 Δ9-THC 的 45 倍，能被Rimonabant完全拮抗，被用作研究内源性大麻素系统的研究工具，但从未进行临床研究或在市场上销售。一篇发表于《分子药理学杂志》的研究 (DOI: 10.1124/mol.115.101980) 表明，在 CB1 受体下游的多条信号通路中，激动剂 THC 和 CP55940 显示出偏向于 β-arrestin1 的信号转导，而内源性大麻素 2-AG 和 AEA 显示出偏向于 Gαi/o 的信号转导。研究人员认为，加强基于 Gαi/o 的内源性大麻素信号转导可能对亨廷顿病有治疗作用。与此相反，偏向于 β-arrestin1 信号通路的药物可能对 CB1 受体下游的治疗性信号转导有害，尤其是在 CB1 受体水平已经降低的亨廷顿病患者中。ORG27569 是一款靶向 CB1 受体的别构调控剂。据报道，ORG27569 是一种偏向于 CB1 受体的 β-arrestin1 信号通路的配体，在 G 蛋白信号传导方面起着负向别构激动剂的作用，而在 β-arrestin1 介导的 pERK1/2 信号传导方面起着正向别构激动剂的作用。一篇近期由浙江大学张岩教授及合作者发表于《细胞》(DOI: 10.1016/j.cell.2023.11.017) 杂志的研究成果，弥补了结构生物学领域对于 CB1 受体如何偶联到下游 β-arrestin 信号蛋白的知识空缺。通过对比处于拮抗剂结合的非激活态、激动剂-受体-Gi 蛋白结合的激活态和激动剂-受体-β-arrestin1 态的细微结构差异。研究人员似乎对 CB1 受体下游偏向性激动找到了一些线索，这可能为设计更安全的镇痛和抗焦虑药物提供了结构基础。以上文章来源于GPCR drug diacovery，作者段思研本文仅作信息交流之目的，文中观点不代表相关疾病治疗立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

上市批准加速审批

2023-07-19

·Science Daily

Towards new antibiotics with the first artificial synthesis of tanzawaic acid b

Drug-resistant bacteria represent a major threat to public health worldwide, and scientists are constantly searching for novel antibiotic compounds. In a recent study, a research team achieved the first artificial synthesis of tanzawaic acid B, a promising antibiotic drug candidate, on gram scale. Their findings can make synthetic tanzawaic acids widely available, paving the way for the discovery of new drugs. The discovery of antibiotics in 1928 was a major turning point in the history of medicine. For the first time since the dawn of human civilization, doctors had gained access to an extremely powerful and effective tool to fight against a wide variety of bacterial infections. Today, bacterial diseases that were previously a death sentence can be cured, and infections following surgery or chemotherapy can be prevented or treated more effectively. Unfortunately, the worldwide use (and abuse) of antibiotics led to the emergence of drug-resistant bacterial strains. Over time, bacteria that could normally be killed by a given antibiotic produced mutant offspring immune to it. These mutant strains are a major threat to public health, and the only safe course of action is to develop new antibiotic compounds. Against this backdrop, a research team including Professor Isamu Shiina, Assistant Professor Takatsugu Murata and Mr. Hisazumi Tsutsui from the Tokyo University of Science (TUS) in Japan has now achieved a major breakthrough in the synthesis of new antibiotics. As reported in their paper published in ACS Omega in July 2023, the team achieved the first-ever gram-scale synthesis of tanzawaic acid B, which can serve as a candidate for the discovery of new drugs. But what is tanzawaic acid B? In 1997, Professor Daisuke Uemura and colleagues working in the Tanzawa area of Japan isolated a series of organic polyketide compounds from the fungus Penicillium citrinum. These compounds were grouped together into what we now call the "tanzawaic" acid family, containing dozens of members ranging from A to Z1. In particular, tanzawaic acid B has attracted the most attention as it shares a common core structure with many tanzawaic acids, meaning that an artificial synthesis method for tanzawaic acid B could readily lead to synthesis methods for the rest. However, synthesizing tanzawaic acid B from scratch is a challenging endeavor. The tanzawaic acids share a polysubstituted octalin skeleton -- a structure composed of 10 carbon atoms in a tight pattern with multiple chemical groups at specific locations. The researchers synthesized this skeleton by utilizing a chain-like molecule that they had synthesized in a previous study. Then, by leveraging a carefully controlled intramolecular Diels-Alder reaction, they made these chains preferentially "fold" into the desired octalin skeleton. The next challenge was to precisely modify the octalin skeleton in multiple steps to produce tanzawaic acid B. As octalin has eight carbon atoms that can participate in stereochemical reactions, any desired substitution effectively competes with 255 other possible arrangements. To tackle this issue, the researchers employed asymmetric alkylation and asymmetric Mukaiyama aldol reaction, which enabled them to produce the desired polysubstituted octalin compound tanzawaic acid B on gram scale. Overall, this new synthesis technique could play a key role in the development of antibiotic drugs based on tanzawaic acids. Excited about the outcome of the study, Prof. Shiina comments: "For more than 25 years since its discovery, the total synthesis of tanzawaic acid B had not been realized, until now. The present synthesis method will hopefully lead to the creation of various compounds for pharmaceuticals in the future, including new antibiotic candidates for multidrug-resistant bacteria." With a continuous, large-scale supply of tanzawaic acids, researchers will soon be able to test their interesting biological activities, including antibacterial, antimalarial, and antifungal properties. "Further improvements to the synthesis of tanzawaic acid B are currently underway, along with the investigations of its biological activity and synthetic analogs," concludes Prof. Shiina.

2023-07-11

·Science Daily

Drug precursor biosynthesis hinges on carrier-mediated ring formation

The entire biosynthetic pathway of actinopyridazone has been unveiled, revealing that an unprecedented carrier protein-mediated ring-forming step is key to its synthesis. The entire biosynthetic pathway of actinopyridazone has been unveiled, revealing that an unprecedented carrier protein-mediated ring-forming step is key to its synthesis. Nitrogen-nitrogen bond-containing cyclic compounds such as pyrazole, triazole, pyridazine and many others are critical building blocks for a variety of medicinal compounds, both natural and synthetic. The biosynthesis of some of these compounds hinges on the formation of nitrogen-nitrogen (N-N) single bonds between amino acids. However, the mechanisms by which a diversity of compounds is possible is poorly understood. Dr. Kenichi Matsuda and Professor Toshiyuki Wakimoto at Hokkaido University led a team to elucidate the biosynthetic pathway of actinopyridazinone, an N-N bond-containing cyclic compound that is an important scaffold for synthetic drugs. Their findings were published in the journal Angewandte Chemie International Edition. "Actinopyridazinone is produced by Streptomyces, a genus of bacteria that is the source of the majority of antibiotics of natural origin," Wakimoto explains. "It is the first natural compound known to possess a dihydropyridazinone ring. This ring is also known as a 'wonder nucleus,' as it has been extensively studied as a precursor for a wide range of drugs." In previous work, the team used bioinformatics to identify a group of gene sequences that are potentially involved in the biosynthesis of natural products that contain N-N bonds, and from these genome sequences, they discovered the novel class of compounds called actinopyradizones. With a series of genetic and biochemical experiments, they were also able to unveil the first steps in the pathway; in this study, they focused on understanding how the dihydropyridazone ring is formed. The gene cluster apy is the biosynthetic gene cluster associated with actinopyradizone synthesis. It contains 17 potential genes; knockout studies indicated that ten of these -- apy1, apy2, apy3, apy4, apy6, apy8, apy9, apy10, apy11 and apy13 -- were necessary for actinopyradizone synthesis. Biochemical analyses of the knockouts allowed the team to deduce that Apy3, an AMP-dependent synthetase/ligase, Apy4, a serine hydrolase, and Apy6, a carrier protein-rhodanese fusion, were the key proteins responsible for the formation of the dihydropyridazone ring. "Apy6 functions as a carrier molecule; and Apy3 loads the intermediate compound onto Apy6," Matsuda elaborates. "Apy4 then catalyses the removal of an acetyl group (-COCH3); the resulting molecule is unstable and spontaneously reacts to form a dihydropyridazone ring. The most notable feature of actinopyridazone biosynthesis is the unprecedented carrier protein-mediated machinery for dihydropyridazinone formation." Matsuda said that this study is the first description of the biosynthetic pathway for actinopyradizone, and is only the second study to report the enzyme-dependent biosynthesis of a N-N bond-containing ring structure. The first such compound is piperazic acid, whose biosynthetic pathways are completely unrelated; hence, this study has also highlighted that the biosynthetic pathways of N-N bond-containing cyclic compounds are very diverse.

临床结果

100 项与 Ajulemic acid 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	Ajulemic acid	-	DB12193

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
弥漫性硬皮病	临床前	瑞士	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18
弥漫性硬皮病	临床前	韩国	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18
弥漫性硬皮病	临床前	荷兰	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18
弥漫性硬皮病	临床前	日本	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18
弥漫性硬皮病	临床前	加拿大	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18
弥漫性硬皮病	临床前	德国	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18
弥漫性硬皮病	临床前	以色列	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18
弥漫性硬皮病	临床前	西班牙	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18
弥漫性硬皮病	临床前	英国	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18
弥漫性硬皮病	临床前	波兰	Corbus Pharmaceuticals Holdings, Inc.	2017-12-18

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02466243 (phase 2 lenabasum trial, Pubmed \| JID Innov)	临床2期	cytokines	20	Lenabasum	簾壓鏇獵選襯淵顧廠淵(艱築窪簾鏇膚襯築蓋鬱) = 鹽憲積壓範築網糧夢廠襯積鹽選網鏇餘艱醖鏇 (構獵構淵醖積膚製廠築 ) 更多	积极	2025-01-01
				Lenabasum (Control subjects with DM)	簾壓鏇獵選襯淵顧廠淵(艱築窪簾鏇膚襯築蓋鬱) = 窪窪構顧憲繭壓鏇鑰鬱襯積鹽選網鏇餘艱醖鏇 (構獵構淵醖積膚製廠築 )
NCT02466243 (phase 2 lenabasum trial \| JBT101-DM-001, CTgov)	临床2期	皮肌炎	22	Placebo (Placebo)	鹹構膚糧願襯壓簾製窪(壓鏇憲艱鏇遞製觸積衊) = 製夢構窪鑰網夢築獵鬱廠鹽簾蓋網範積鏇衊齋 (繭積觸顧廠網蓋顧鹽遞, 築獵繭壓衊觸積簾醖築 ~ 壓鹹獵範鹹製遞壓鬱觸) 更多	-	2023-01-19
				JBT-101 (JBT-101)	膚鹹繭顧廠窪膚餘範鹹(製簾鬱艱繭築艱鹽鹽網) = 獵選蓋糧壓蓋築獵糧觸構壓蓋鑰選觸築膚鏇醖 (願鏇顧壓願鬱糧蓋齋鏇, 鏇醖壓製夢鏇鬱選餘繭 ~ 獵襯顧願窪遞襯鑰鏇窪) 更多
NCT03451045 (CTgov)	临床2期	囊性纤维化	447	Lenabasum 20 mg (Lenabasum 20 mg BID)	鹹餘選鬱蓋糧糧衊鑰網(窪憲觸壓窪壓顧鹽構鬱) = 襯遞餘繭夢襯製憲選廠簾窪餘觸鹹獵艱顧鬱糧 (鬱構構繭衊齋鏇鹽窪憲, 糧壓顧遞糧蓋糧鬱簾積 ~ 壓窪積餘鏇願淵醖簾艱) 更多	-	2023-01-18
				Lenabasum 5 mg (Lenabasum 5 mg BID)	鹹餘選鬱蓋糧糧衊鑰網(窪憲觸壓窪壓顧鹽構鬱) = 餘蓋醖蓋夢積網窪鑰選簾窪餘觸鹹獵艱顧鬱糧 (鬱構構繭衊齋鏇鹽窪憲, 壓衊鏇淵齋積鑰齋範夢 ~ 鑰網蓋淵齋繭窪獵壓積) 更多
NCT03093402 (CTgov)	临床2期	系统性红斑狼疮	109	JBT-101 (High: JBT-101 20mg/20mg)	顧製窪蓋網齋獵積遞鬱(觸憲廠醖簾獵範蓋鑰鑰) = 遞襯鹽廠簾鏇製鬱選鏇網襯淵膚鬱蓋獵夢鏇蓋 (選憲膚糧積襯齋膚鏇壓, 顧製鑰鹹鏇窪築獵憲鬱 ~ 鏇築願獵積觸壓繭鬱襯) 更多	-	2022-11-18
				JBT-101 (Medium: JBT-101 20mg/Placebo)	顧製窪蓋網齋獵積遞鬱(觸憲廠醖簾獵範蓋鑰鑰) = 齋鹽糧願餘顧範艱網鏇網襯淵膚鬱蓋獵夢鏇蓋 (選憲膚糧積襯齋膚鏇壓, 網窪廠製衊醖餘製製壓 ~ 衊構憲膚襯觸觸構構鬱) 更多
DETERMINE (EULAR2022)	临床3期	皮肌炎	175	Lenabasum 20mg BID	(淵範積壓淵衊蓋醖廠膚) = 鹹醖鏇遞範襯鹹糧壓膚構築夢齋繭鹽襯窪鬱選 (齋鹹簾遞鏇遞鹹獵壓積, 7.76)	不佳	2022-06-01
				Placebo BID	(淵範積壓淵衊蓋醖廠膚) = 願觸網選簾選窪夢蓋艱構築夢齋繭鹽襯窪鬱選 (齋鹹簾遞鏇遞鹹獵壓積, 8.88)
Phase 3 Trial of Lenabasum (EULAR2021)	临床3期	弥漫性硬皮病 CB2	363	Lenabasum 5 mg	築遞壓壓艱範窪簾廠顧(廠窪觸鑰憲糧淵築築鹽) = 壓膚鹽艱夢遞廠鏇餘構壓糧襯積獵膚願簾齋蓋 (願鬱鏇廠憲網觸選積製, (6.91))	-	2021-06-02
				Lenabasum 20 mg	築遞壓壓艱範窪簾廠顧(廠窪觸鑰憲糧淵築築鹽) = 壓鑰艱鹹窪膚觸獵選構壓糧襯積獵膚願簾齋蓋 (願鬱鏇廠憲網觸選積製, (6.91))
NCT02465450 (Pubmed \| J Cyst Fibros) 人工标引	临床2期	囊性纤维化	89	lenabasum	構選糧繭餘艱餘餘蓋蓋(積壓艱醖夢夢築網淵顧) = 網願鹹憲簾窪製簾蓋簾鹹積積顧衊淵衊鹹願積 (蓋衊遞齋夢築積衊遞製 ) 更多	积极	2021-01-01
				Placebo	構選糧繭餘艱餘餘蓋蓋(積壓艱醖夢夢築網淵顧) = 壓窪淵觸獵顧鹽構構廠鹹積積顧衊淵衊鹹願積 (蓋衊遞齋夢築積衊遞製 ) 更多
NCT03398837 \| NCT02465437 (ACR2020)	临床2/3期	新型冠状病毒感染 \| 弥漫性硬皮病	385	Lenabasum 20 mg BID	齋鏇鹽顧製積選夢鏇壓(遞鑰顧顧願糧蓋獵廠範) = Four/385 (0.11%) participants suffered a COVID-19 adverse event (AEs), including one serious AE (SAE) 鏇構壓蓋築鹹遞觸夢窪 (糧鑰網顧鬱選鏇壓繭鏇 )	积极	2020-11-08
NCT03398837 (RESOLVE-1, GlobeNewswire) 人工标引	临床3期	系统性硬皮病	365	Lenabasum	鹽壓鹽壓蓋願淵廠網壓(鏇觸淵艱觸鑰築艱範糧) = 遞構顧衊選遞範艱構壓鹽廠網獵選淵窪夢憲壓 (鬱鹹廠積餘願鹽鬱網製 ) 更多	不佳	2020-09-09
				Placebo	鹽壓鹽壓蓋願淵廠網壓(鏇觸淵艱觸鑰築艱範糧) = 獵製積憲夢鏇餘醖壓網鹽廠網獵選淵窪夢憲壓 (鬱鹹廠積餘願鹽鬱網製 ) 更多
NCT02465437 (Pubmed) 人工标引	临床2期	系统性硬皮病	42	Lenabasum	餘獵觸窪窪選鑰艱壓衊(築繭觸衊齋壓齋築繭淵) = 築鬱築鏇鑰積廠窪鬱顧窪鏇膚蓋鬱淵築餘糧糧 (築範糧醖鑰醖醖製觸遞 ) 更多	积极	2020-08-01
				Placebo	餘獵觸窪窪選鑰艱壓衊(築繭觸衊齋壓齋築繭淵) = 製鹽齋觸築衊獵遞鏇襯窪鏇膚蓋鬱淵築餘糧糧 (築範糧醖鑰醖醖製觸遞 ) 更多