Pimodivir

最近看到一篇18年在JMC发表的文章《What Makes a Great Medicinal Chemist? A Personal Perspective》，作者是Mark A. Murcko博士。Mark是Relay Therapeutics的co-founder和CSO，也是Dewpoint Therapeutics的董事会成员。2011年11月之前，Mark一直担任Vertex的CSO兼科学顾问委员会主席，负责整个研发过程中颠覆性技术的识别、验证和实施。Mark是HCV蛋白酶抑制剂 Incivek (telaprevir) 以及 Vertex 的两种上市治疗 HIV 药物 Agenerase (amprenavir) 和 Lexiva (fosamprenavir) 的共同发明人。此外，他还指导和支持 Vertex囊性纤维化项目的早期工作，该项目已生产四种上市药物：Kalydeco (ivacaftor)、Orkambi (lumacaftor/ivacaftor)、Symdeco (tezacaftor/ivacaftor) 和 Trikafta (elexacaftor/ tezzacaftor/ ivacaftor) 。在加入Vertex之前，Mark曾在MSD工作，帮助发现了多种临床候选药物，包括用于治疗青光眼的碳酸酐酶抑制剂多佐胺（Trusopt）。Trusopt是制药史上第一个由基于结构的药物设计程序产生的上市药物。此前已有公众号文章《如何成为一名伟大的药物化学家？》介绍了这篇文章的内容，重复的内容这里感觉没必要多介绍了。因此本系列是根据文章的内容，补充一些背景知识。Discipline-Specific Characteristics of Medicinal Chemists:1）总是在考虑目标产品概况（TPP）。出色的药化学家总是有一个明确的“目标产品概况”（TPP）。清晰的TPP可以让药化学家清楚地了解分子何时在各个方面都“足够好”，可以继续前进。在Vertex的HCV蛋白酶抑制剂（Telaprevir）项目中，科学家有意识地寻找能够优先分布到HCV感染的主要部位（肝脏）的化合物，从而通过降低全身暴露来潜在降低全身毒性。大鼠的PK研究表明，Telaprevir在肝脏中的浓度相对于血浆明显更高，平均浓度（0-8小时）分别为9.82 ± 5.00 μg/g和0.28 ± 0.19 μg/ml，比率为35：1。NS3-4A蛋白酶是一种具有胰凝乳蛋白酶样折叠的丝氨酸蛋白酶，但在高通量筛选中没有发现hit。NS3-4A蛋白酶的活性位点极其疏水、平坦且暴露于溶剂，几乎没有口袋。拟肽抑制剂的初步研究始于截短源自天然NS5A-5B底物的十肽抑制剂（1），且从C或N末端减少1-2个氨基酸的长度会显著降低结合亲和力。这表明天然底物分布在较大的表面积上，与HCV蛋白酶结构域与十肽的共晶结构一致。随后发现HCV蛋白酶可以被其自身的裂解产物抑制，认识到需要限制分子量以获得类药的特性，十聚体抑制剂被截短为P4至P1'子位点，尽管效力有所损失。为了增加亲和力，引入共价弹头开发了可逆共价抑制剂四醛肽（2），以优化化合物与活性位点的结合。用α-酮酰胺代替醛弹头（3），由于离子相互作用增加和半衰期更长，因此结合亲和力显著提高。随后α-酮酰胺化合物优化得到双环（4）。由于蛋白酶会根据与其结合的抑制剂而改变构象，因此很难一次优化一个亚位点并“锁定”它。P1'、P1、P3和P4结合亚位点的进一步优化和酮的还原后得到Telaprevir。尽管可逆共价抑制机制有可能增加Telaprevir对其他丝氨酸蛋白酶的脱靶抑制风险，但特拉匹韦对凝血酶、胰凝乳蛋白酶、胰蛋白酶、纤溶酶和激肽释放酶的选择性超过500倍。Nature Biotechnology 29, 993–1003 (2011)2）creative drug designers。case 1）Merck-Frosst的组织蛋白酶K项目中用三氟乙胺基团作为酰胺电子等排体，避免分子在溶酶体中浓缩，从而提高了口服生物利用度。三氟乙基可以取代酰胺的羰基并生成代谢稳定的弱碱性胺，从而保持酰胺优异的氢键。case 2）将硼纳入药物设计为可逆共价抑制剂的制作提供了一种新颖且富有创意的弹头，上市药物包括蛋白酶体抑制剂硼替佐米和第二代药物伊沙佐米，以及抗真菌药物他伐硼罗。B原子有一个空的P轨道，可与O和N的孤对电子形成配位键，但与S成的键却很弱，因此可以选择性抑制蛋白酶体（活性位点有丝氨酸或苏氨酸）。3）管理化合物的特性。出色的药化学家并不专注于药效，而是全局统筹分子特性；同时，也不盲从“规则”。例如亲脂性过大可能会带来挑战，但专注于优化正确的特性，大的、复杂的、亲脂性的化合物也可以成为药物。最出名的案例应该是HCV NS5A抑制剂，最开始发现的hit的分子量在750-900范围内，logP值高达8。NS5A是一种锌结合蛋白二聚体，是HCV复制周期的调节因子。NS5A是七种非结构蛋白之一，它们与受感染细胞内的病毒RNA形成复合物以启动HCV复制。第一个获批的NS5A抑制剂是daclatasvir (Daklinza)，与asunaprevir联合用药于2014年7月在日本首次批准。Daclatasvir于2015年7月获FDA批准。另一款NS5A抑制剂ledipasvir的上市时间也非常接近，于2014年10月获FDA批准与索磷布韦联合组成 HCV 药物Harvoni。下图是目前上市的NS5A抑制剂的分子结构，可以明显看出其它分子都是在daclatasvir的结构基础上改造的。值得一提的是，daclatasvir是在没有靶标结构的基础上，靠药化学家的经验优化得到的FIC，详情可查看郭宗儒老师的文章《药物化学原理与方法研制的达卡他韦》。4）think in three dimensions. 即使没有靶标结构，出色的药化学家也会不断想象他们的分子在3D中的样子，无论是在水里还是在脂质中、在细胞外还是在细胞内、与受体结合或游离时。他们欢迎任何有助于可视化分子并了解其构象偏好的信息。这里，作者简单介绍了UCSF的Jacobson实验室用物理模型预测膜渗透性的工作。值得一提的是，Jacobson和作者都是Relay的founder，目前Jacobson已不在UCSF全职，而是专心创业了。5）准备好不同分子骨架。PK、毒性、合成和IP等往往是不可预测的。拥有第二种、新颖的、表现良好的分子骨架通常是确保成功的最佳方法。作者的印象是，有些组织除非确定了第二个有希望的分子骨架，否则不会宣布项目处于lead optimization阶段。6）不会对IP感到恐慌。有很多靶标如HMGCoA还原酶、血管紧张素转换酶、血清素、血管紧张素 II 受体、H2受体、PDE5、HIV-1蛋白酶、HCV蛋白酶和HCV-NS5A，有多款不同分子骨架的上市药物。虽然针对同一靶标的不同化合物通常具有一些共同特征，但每个研究团队都在化学空间中开辟了一些独特的“角落”，尽量让自家的上市分子有自己的差异化优势。作者在这里举的靶标相对较老，结合国内最近的license out案例，很多国内药企在老靶点上做出了差异化。比如恒瑞的PARP1抑制剂《恒瑞的PARP1抑制剂HRS1167的药物设计》、安锐生物的CDK2抑制剂《超10亿美元授权，安锐生物CDK2抑制剂ARTS-021长啥样？》和赞荣医药的HER2抑制剂《与Roche达成6.8亿美元交易背后，赞荣医药的HER2抑制剂的药物设计》。7）不会放弃经过验证的靶标。在传染病领域，靶标在传染原生命周期中的重要作用的置信度可以接近100%。因此，即使在化学挑战巨大的情况下，团队也有勇气坚持下去。代表性例子包括HIV-1蛋白酶、HIV-1整合酶、HCV蛋白酶和HCV-NS5A。除了传染病之外，一个经典案例是先灵葆雅公司的凝血酶受体（PAR-1）拮抗剂沃拉帕沙 (vorapaxar) 。从天然产物Himbacine（一种早期非肽拮抗剂，从木兰科植物中分离的生物碱）的全合成开始，第一个候选物被发现会引起CYP诱导，第二个则是会在猴子体内积累。但该团队并没有放弃，最终发现了第三个候选药物SCH-530348（vorapaxar）。而苦难还没有结束。该药物在2011年由于脑出血增加问题，默克公司暂停了针对中风和轻度心脏病患者的III期临床试验；后来在曾经历过心脏病、中风或外周动脉疾病的患者中进行了研究，发现该药物可以减少心血管终点事件，最终于2014年获得批准。另一个案例是口服碳酸酐酶抑制剂 (CAI) 。CAI可以降低眼内压并治疗青光眼，但此前的CAI都是全身给药因此副作用较大。要制成滴眼剂需要分子有足够的水溶解性和一定亲脂性以透过角膜, 所以需要平衡好分子的logP。MSD团队参考口服药物acetazolamide和ethoxzolamide的片段，从噻吩磺酰胺骨架出发，优化出噻吩并硫代吡喃骨架，再对侧链调整最终得到多佐胺（logP = -0.5）。详情可查看郭宗儒老师的文章《基于碳酸酐酶结构设计的滴眼剂多佐胺》。8）非常关心生物学。作者提到Vertex的细胞生物学家Tim Neuberger，Tim多年来一直在努力利用囊性纤维化患者培养的人支气管上皮细胞开发经过验证的药理学模型。9）很清楚下一步要做什么。这里作者举了VX-787的案例，遗憾的是该药物的3期临床失败了。在初期的表型筛选和后期的SBDD阶段，团队确切地知道他们需要合成什么化合物，以及如何最好地利用现有数据来支持他们的决策。10）不畏惧复杂的合成。出色的药物化学家总是避免不必要的复杂性，但有时最好的分子很难合成。作者举了卫材的Halaven（甲磺酸艾日布林）的商业化生产案例。艾日布林于2010年获FDA批准，用于治疗转移性乳腺癌。2022年的销售额超过3.5亿美元。艾日布林含有19个立体中心，是目前市场上全合成制备的结构最复杂的原料药。经过多年的努力，卫材团队在Kishi团队在相关软海绵素所做的工作基础上，开发了一种可扩展的62步合成方法。11）尽可能地重复利用一切。drug hunter会毫不客气地重新利用任何东西（整个分子、骨架、官能团、合成方法、分析、动物模型），他们的重点不是新颖性本身，而是做任何制造药物所需的事情。Vertex的IL1β 转换酶（ICE；caspase-1）项目是一个代表性案例。1994年初团队得到了ICE的晶体结构与四肽醛共价抑制剂，并试图从各种肽模拟设计策略中进行选择。Guy Bemis注意到ICE的活性位点与胰凝乳蛋白酶折叠蛋白的活性位点非常相似。这完全是出乎意料的，因为caspase-1的整体折叠与胰凝乳蛋白酶完全不同。ICE肽抑制剂形成与胰凝乳蛋白酶家族丝氨酸蛋白酶抑制剂中常见的相同氢键模式并采用相同的主链构象。根据Guy的观察，药化小组组长Michael Mullican优先考虑了一系列双环S2-S3拟肽骨架，这些骨架已成功用于抑制其他丝氨酸蛋白酶，包括哒嗪并二氮杂卓类药物。这项工作催生了VX-740（pralnacasan），但并没有成功上市。12）了解药物发现的历史。

It was a busy week for both COVID-19-related clinical trial news and the rest of the industry. Here’s a look. It was a busy week for both COVID-19-related clinical trial news and the rest of the industry. Here’s a look. COVID-19-Related Vir Biotechnology and GlaxoSmithKline dosed the first patient last week in a Phase II/III clinical trial of VIR-7831, a fully human monoclonal antibody against COVID-19. The trial is evaluating therapy as early treatment for COVID-19 patient at high risk of hospitalization. The Vir-GSK COMET-ICE study plans to enroll about 1,300 patients globally who have early symptoms of infection. The goal is to evaluate VIR-7831, a single-dose monoclonal antibody, to see if it can prevent hospitalization from the disease. They expect results before the end of the year with complete data in the first quarter of 2021, and possibly early access to treatment in the first half of 2021. FSD Pharma submitted an IND for FSD201 (ultramicronized palmitoylethanolamide, or ultramicronized PEA) to treat COVID-19. FSD201 is being developed for its anti-inflammatory properties to avoid the cytokine storm linked with acute lung injury in hospitalized COVID-19 patients. The Phase II trial will be run at 25 to 30 sites in North America. Orpheris , a subsidiary of Ashvattha Therapeutics, enrolled the first patients in its Phase II PRANA clinical trial of OP-101 in severe COVID-19. OP-101 is designed to target and shut down all proinflammatory pathways and restore macrophages to a normal, anti-inflammatory state. AstraZeneca announced that its Phase III clinical trial of its COVID-19 vaccine candidate, AZD1222, is expanding into the U.S. It will be dubbed D8110C00001 and is funded by the Biomedical Advanced Development Authority (BARDA) and the National Institute of Allergy and Infectious Diseases (NIAID). The NIAID-supported COVID-19 Prevention Network (CoVPN) is also participating. The U.S. expansion will recruit up to 30,000 adults over the age of 18 years from a broad range of racial, ethnic and geographic groups who are healthy or have stable underlying medical conditions. This will also include patients with HIV, who are at increased risk from COVID-19 infections. Clear Creek Bio dosed the first patient in a Phase I clinical trial of brequinar in COVID-19 patients. Brequinar is an oral, potent and selective small molecule DHODH inhibitor that blocks host cell de novo pyrimidine biosynthesis, which is needed for DNA and RNA synthesis. It appears to have potent antiviral activity. Biophytis enrolled the first patient in COVA, a Phase II/III trial of sarconeos (BIO101) for patients with COVID-19-related respiratory failure. It has five centers recruiting patients in Belgium, France and the U.S. Sarconeos is an oral small molecule being developed in Phase IIb in sarcopenia, as well as Duchenne muscular dystrophy (DMD). The drug activates the MAS receptor, a key component of the protective arm of RAS, the renin angiotensin system, which plays a key role in regulating respiratory function. Sanofi announced that its Phase III trial of IV Kevzara (sarilumab) at a dose of 200mg or 400mg in severely or critically ill patients hospitalized with COVID-19 did not meet its primary endpoint and key secondary endpoint compared to placebo. Kevzara is approved to treat adults with moderately to severely active rheumatoid arthritis. It binds to the IL-6b receptor and inhibits IL-6 mediated signaling. INmune Bio got the go-ahead from the FDA to initiate a Phase II trial of Quellor, a selective soluble tumor necrosis factor (sTNF) inhibitor, for the immune mediated complications in COVID-19 patients. The blinded randomized Phase II trial will enroll 366 COVID-19 patients in two equal sized cohorts, standard of care, which may include remdesivir, or SOC plus Quellor. A second dose of Quellor may be given a week later if the patient remains hospitalized. Organicell Regenerative Medicine reported that the FDA granted emergency, expanded access to treat two mild to moderate COVID-19 patients and one “long hauler” post COVID-19 patient with Zofin. The company plans to begin patient enrollment in a Phase I/II trial to evaluate the drug in moderate to severe COVID-19 patients. Zofin is a nanoparticle-based therapy derived from perinatal sources and designed to retain microRNAs. Aerpio Pharmaceuticals and Quantum Leap Healthcare Collaborative dosed the first patient with razuprotafib in the Phase II I-SPY COVID Trial in hopes of improving ARDs in severely ill COVID-19 patients. Razuprotafib is a first-in-class small molecule inhibitor of vascular endothelial protein tyrosine phosphatase and is also being developed for open angle glaucoma and other indications. City of Hope is initiating a Phase I trial of rheumatoid arthritis drug leflunomide in COVID-19 patients. Patients treated for cancer in the last two years may also be eligible. The overall focus is on cancer patients who are being treated for COVID-19. GlaxoSmithKline and Sanofi are beginning a Phase I/II clinical trial of their COVID-19 vaccine that uses GSK’s pandemic adjuvant technology. It will include 440 healthy adults be run at 11 separate sites. Non-COVID-19-Related AstraZeneca ’s Farxiga (dapagliflozin) dramatically prolonged survival in patients with chronic kidney disease in a Phase III clinical trial. Specifically, Farxiga with standard of care decreased the composite measure of worsening of renal function or risk of cardiovascular (CV) or renal death by 39% compared to placebo. This was in patients with chronic kidney disease (CKD) Stages 2-4 and elevated urinary albumin excretion. There were no differences observed in patients who had or did not have type 2 diabetes. Akcea Therapeutics and Ionis Pharmaceuticals presented data from the Phase II study of AKCEA-APOCIII-LRx. The therapy met primary and key secondary endpoints with significant decreases in triglyceride and apoC-III levels. AKCEA-APOCIII-LRx is designed using Ionis’ Ligand Conjugated Antisense (LICA) technology platform to inhibit production of apolipoprotein C-III, a protein generated in the liver that plays a primary role in the regulation of serum triglycerides. UCB published the results of the Phase III VIMPAT (lacosamide) CV as adjunctive treatment for uncontrolled primary generalized tonic-clonic seizures (PGTCS). The trial enrolled 242 patients with idiopathic generalized epilepsy. The primary endpoint was time to second PGTCS during the 24-week treatment period. Treatment with locasamide demonstrated a significantly lower risk of developing a second PGTCS and a significantly higher rate of freedom from PGTCS during the period compared to placebo. It was approved in the U.S. in 2008 as an add-on therapy for adult patients, then as a monotherapy in adults in August 2014, and in 2018, as monotherapy or adjunctive therapy in patients four years of age and older with partial-onset seizures. Eisai announced data from several post hoc analyses of Dayvigo from the Phase III SUNRISE 1 and 2 trials and topline results from an open label pilot study. The studies evaluated the transition of insomnia patients from zolpidem to Dayvigo, with generally positive results. Dayvigo (Lemborexant) is a small-molecule orexin receptor antagonist. Novartis announced results from a post-hoc analysis of pooled data from the Phase III ORION-10 and -11 trials evaluating individual responses of patients on low-density lipoprotein cholesterol reduction with inclisiran. Inclisiran is a first-in-class investigation treatment for hyperlipidemia in adults. The new data showed a highly consistent effect with a similar safety pro placebo. Boehringer Ingelheim and Eli Lilly announced full results from the EMPEROR-Reduced Phase III trial in adults with heart failure with reduced ejection fraction, with and without diabetes. This showed that Jardiance (empagliflozin) was associated with a 25% relative risk reduction in the primary endpoint of time to cardiovascular death or hospitalization due to heart failure. Acasti Pharma announced topline data from its Phase III TRILOGY 2 trial of CaPre (omega-3 phospholipid) to reduce severe triglyceride levels. The primary endpoint was triglyceride reduction at 12 and 26 weeks. The trial evaluated 278 patients. Patients receiving CaPre demonstrated a 30.4% median reduction in triglyceride levels compared to 30.5% in TRILOGY 1, and a 17.9% median reduction in triglyceride levels in patients receiving placebo at 12 weeks compared to 27.5% in TRILOGY 1. The company indicated that the unadjusted, placebo corrected triglyceride reduction of 12.4% achieved a “p” value of 0.19, which was not statistically significant—as a result, TRILOGY 2 did not meet the primary endpoint. Mirum Pharmaceuticals presented new data from its Phase II INDIGO trial. It was a five-year analysis that demonstrated that patients with PFIC2, also called bile salt export pump (BSEP) deficiency, who achieved serum bile acid (sBA) control on long-term maralixibat treatment have a significant improvement in transplant-free survival. Bristol Myers Squibb announced interim data from the Phase III open-label extension trial DAYBREAK. The data demonstrated the long-term efficacy and safety pro Zeposia (ozanimod) in relapsing forms of multiple sclerosis (MS). The trial included 2,494 patients who had previously completed a Phase I, II or III Zeposia trial and who had an average treatment time of 35.4 months while in DAYBREAK. No new safety concerns were observed. At 2 and 3 years, 79% and 75% of patients, respectively, were relapse-free and 3- and 6-month confirmed disability progression was observed in 10.8% and 8.6% of participants, respectively. Oxurion NV dosed the first patient in its two-part Phase II trial KALAHARI. It is evaluating THR-149 for the treatment of diabetic macular edema (DME). THR-149 acts via inhibition of the Plasma Kallikrein-Kinin (PKal-Kinin) system, a validated VEGF independent target for DME. Janssen Pharmaceutical of Johnson & Johnson made a strategic call to halt development of pimodivir, an antiviral treatment for influenza A. The decision was based on data from a pre-planned interim analysis of the Phase III trial of pimodivir in hospitalized influenza A patients. The analysis suggested that the drug in combination with standard of care (SOC) was “very unlikely” to show added benefit in the patient population over SOC alone. Akebia Therapeutics announced topline results for PRO 2 TECT, the second of two Phase III cardiovascular outcomes programs. The trial was evaluating the company’s vadadustat for treatment of anemia caused by chronic kidney disease in adults not on dialysis. In the two PRO 2 TECT studies, vadadustat hit the primary and key secondary efficacy endpoint, which was non-inferiority to darbepoetin alfa. This was measured by a mean change in hemoglobin (Hb) between baseline and the primary evaluation period, weeks 24 to 36 and the secondary evaluation period at weeks 40 to 52. However, the drug did not meet the primary safety endpoint of the PRO 2 TECT program. This was defined as non-inferiority of vadadustat compared to darbepoetin alfa in how long to the first occurrence of major adverse cardiovascular events (MACE). MACE is the composite of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke. Amylyx Pharmaceuticals published data from its Phase II/III CENTAUR clinical trial evaluating AMX0035 in amyotrophic lateral sclerosis (ALS). The research was published in the New England Journal of Medicine. The trial met its primary endpoint, showing a clinically meaningful and statistically significant treatment benefit based on the Revised ALS Functional Rating Scale (ALSFRS-R). The trial evaluated 137 people with ALS and was conducted at 25 medical centers in the U.S. through the Northeast ALS (NEALS) consortium. AMX0035 is a neuroprotective therapy designed to decrease neuronal death and dysfunction. It targets endoplasmic reticulum and mitochondrial dependent neuronal degeneration pathways in ALS.