A Phase I Randomized, Placebo-controlled, Double-blind Study to Assess Safety, Pharmacokinetics, and Modeled Pharmacodynamics of a Vaginal Insert Containing Tenofovir Alafenamide and Elvitegravir

MATRIX-001 will examine the safety, PK, modeled PD, and acceptability of inserts containing the combination of TAF and EVG applied vaginally, daily for 3 days, then every other day for 14 days. The inserts are ultimately intended to be the basis of an event-driven, on-demand method for prevention of HIV and HSV sexual infection.

开始日期2023-11-08

申办/合作机构

Eastern Virginia Medical School

[+3]

NCT03762772

/ Completed临床1期IIT

A Phase I Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of a Vaginal Insert Containing Tenofovir Alafenamide and Elvitegravir

The purpose of this Phase I study is to assess the safety, pharmacokinetics, and pharmacodynamics of a combination vaginal insert containing tenofovir alafenamide (TAF) and elvitegravir (EVG).
This study will be the first-in-human study for a vaginally administered TAF/EVG insert and will evaluate safety, PK and PD after a single dose. It is hypothesized that the combination insert will be safe and well-tolerated by study participants and that the insert will offer an expanded window of preventive activity and a regimen with flexibility and forgiveness.

开始日期2018-12-10

申办/合作机构

Contraception Research and Development

[+1]

NCT02882230

/ TerminatedN/AIIT

Prospective Evaluation of Neurologic and Psychiatric Adverse Events of Rilpivirine, Elvitegravir, or Dolutegravir in a Real Life Setting

The frequency of neurological and psychiatric complaints for participants taking rilpivirine, elvitegravir, or dolutegravir reaches on average 20-30% during clinical trials. The inclusion and exclusion criteria for enrolling people living with HIV are at times so selective and the subsequent descriptions of minor or severe adverse events (AE's) so often imprecise and ambiguous that one cannot extrapolate these particular research results to practicing medicine. These adverse events negatively affect the patient's quality of life and ultimately his or her good adherence to treatments.
This study aims at assessing the prevalence and at describing the neurological and psychiatric adverse events related to these drugs.

开始日期2018-11-19

申办/合作机构

Fondation Ophtalmologique Adolphe de Rothschild

100 项与埃替格韦相关的临床结果

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100 项与埃替格韦相关的转化医学

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100 项与埃替格韦相关的专利（医药）

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1,272

项与埃替格韦相关的文献（医药）

2025-04-02·JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY

Assessing phenotypic effect of integrase strand-transfer inhibitor (INSTI)-based resistance substitutions associated with failures on cabotegravir

Article

作者: Andreatta, Kristen ; D’Antoni, Michelle L ; Falkard, Brie ; Cox, Stephanie ; Cohen, Cal ; Callebaut, Christian

Abstract:

Objectives:

International guidelines recommend integrase strand-transfer inhibitor (INSTI)-based regimens as initial and switch therapy in people with HIV. As novel INSTIs become available, understanding how emergence of resistance at virological failures and seroconversions affects subsequent treatment options is needed. For the latest approved INSTI, cabotegravir, resistance patterns comprising Q148K/R, N155H, R263K, G118R, E138A/K and G140A/S (alone or in combination) have been documented in virological failures and seroconversions. Here, the effect of these substitutions on antiviral activity of commercially approved INSTIs, bictegravir and elvitegravir, was assessed.

Methods:

Antiviral testing was performed using person-derived clinical isolates (n = 52) with viral profiles similar to cabotegravir INSTI resistance patterns; susceptibility to cabotegravir, bictegravir and elvitegravir was measured using a phenotypic assay. Substitution patterns from isolates included triple [Q148K/H/R + E138A/K + G140A/C/S (n = 16)], double [Q148R + E138K (n = 3); Q148H/R + G140A/S (n = 24)] and single [N155H (n = 6); Q148R (n = 3)] resistance-associated mutations (RAMs).

Results:

IC50 fold changes (FCs) for triple RAMs were the highest, at 47.0, 7.59 and >144 for cabotegravir, bictegravir and elvitegravir, respectively. For cabotegravir, bictegravir and elvitegravir, respectively, mean IC50 FCs were 9.5, 2.5 and >144 for double RAMs; and 3.3, 1.4 and >65 for single RAMs. When considering clinical/biological assay cut-offs, 54% (28/52) of isolates were susceptible to bictegravir, 40% (21/52) were partially susceptible and 6% (3/52) were resistant; for elvitegravir, 100% of isolates were resistant. Cabotegravir cut-offs were not available at the time of reporting.

Conclusions:

Overall, clinical isolates with RAM patterns similar to clinically observed cabotegravir INSTI resistance showed meaningful increases in IC50 FCs, suggesting that cabotegravir-associated resistance may negatively affect efficacy of bictegravir- and elvitegravir-based regimens.

2025-03-24·Journal of biomolecular structure & dynamics

Inhibition of respiratory syncytial virus by Daclatasvir and its derivatives: synthesis of computational derivatives as a new drug development

Article

作者: Abdalla, Mohnad ; Mitra, Debanjan ; Afreen, Shagufta ; Das Mohapatra, Pradeep K.

The most common cause of respiratory tract illness in newborns and young children is the respiratory syncytial virus (RSV). There is no approved vaccination or specific antiviral medication for RSV infections. Here, an attempt has been made to explore the potential of currently marketed drugs as well as their probable derivatives to improve the possibility of developing stronger medications against RSV. From the 100 synthetic drug compounds library, the best drug molecule was identified through drug-likeness properties, toxicity, molecular docking and molecular dynamics simulations. Molecular Mechanics Generalized Born Surface Area (MM-GBSA) was also a method that was applied in this study. Daclatasvir showed the highest binding energy and appeared as the best drug to inhibit matrix protein and a fusion protein of RSV. Based on Daclatasvir, 40 computational derivatives were made. D28, D34 and D40 showed far better results than the actual drug. Changes in lipophilicity character increase the binding energy of derivatives. Molecular dynamic simulations showed their non-deviated, non-fluctuated and stable complex formation with target proteins. The high number of amino acid contacts throughout the trajectory increases the stability and effectiveness of derivatives. The key to producing a novel medicine to eradicate RSV is provided by derivatives. Daclatasvir will be employed as a potential RSV inhibitor up until that point.

2025-03-03·JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY

Major role of dolutegravir in the emergence of the S147G integrase resistance mutation

Article

作者: Raymond, Stephanie ; De Monte, Anne ; Bouvier-Alias, Magali ; Calvez, Vincent ; Charpentier, Charlotte ; Pallier, Coralie ; Wirden, Marc ; Marcelin, Anne-Genevieve ; Montes, Brigitte ; Lambert-Niclot, Sidonie ; Abdi, Basma ; Bellecave, Pantxika ; Chaix, Marie-Laure ; Yerly, Sabine ; Descamps, Diane

Abstract:

Background:

The S147G mutation is associated with high-level resistance to the integrase strand transfer inhibitor (INSTI) elvitegravir. In several poorly documented cases, it was also selected in patients on dolutegravir. Given the widespread use of dolutegravir, further studies of S147G are required.

Methods:

We consulted the HIV-1 resistance databases of French laboratories to identify all cases of S147G emergence. We collected immunological and virological parameters, history of treatment and INSTI resistance mutations. Mann–Whitney and Fisher’s exact tests were performed.

Results:

We retrospectively identified 88 cases of S147G selection, from 2015 to 2022, in 22 laboratories. The most frequent HIV-1 subtypes were Clade B (55.7%) and CRF02_AG (21.6%). At the time of resistance genotyping, the median viral load was 5860 copies/mL (IQR 1011–24 525) and the median CD4 cell count was 412 cells/mm3 (228–560). S147G emerged on dolutegravir (48%), elvitegravir (36%) and raltegravir (10%) treatments. S147G was associated with a larger median number of other INSTI mutations on dolutegravir than on elvitegravir [3.0 (2.0–4.0) versus 2.0 (1.0–2.0); P = 0.0002] and was never observed with Q148H or G118R. On dolutegravir, S147G was associated principally with T97A (62%), N155H (59%), E138K (50%), L74I/M (38%) and Q148R (33%).

Conclusions:

In this French study, S147G emerged principally in patients on dolutegravir regimens, in association with up to five other INSTI resistance mutations. This accumulation of mutations suggests a replicative advantage on HIV strains under dolutegravir selection pressure, suggesting that caution is required when interpreting dolutegravir resistance in the presence of such S147G resistance patterns, even in patients prescribed dolutegravir twice daily.

项与埃替格韦相关的新闻（医药）

2025-02-06

·化学经纬

书籍分享||新药化学全合成路线手册

内容介绍本书归纳和综述了新药的化学合成路线。覆盖范围为近5年美国FDA批准上市的新分子实体药共109个。针对每一个药物，本书给出了药物简介，药物化学结构信息，产品上市信息，药品专利保护和市场独占权保护信息，化学全合成路线和参考文献等。这些合成路线大多是目前制药工业中正在使用的化学合成工艺，有较高的实用性和学术价值。对参与反应的起始原料、中间体、反应产物都给出了详细的化学结构。每一步化学合成反应都给出了重要的化学试剂、催化剂、所使用的溶剂、合成反应条件及文献出处等。本书的特点是：作者从浩如烟海的科技文献中，精心挑选出最新、最有实用价值的合成方法，汇编成化学合成路线图，内容简洁，深入浅出，逻辑性强，容易理解，以最少的篇幅表达最多的技术信息，可帮助读者很快找到他们需要的药物合成方法及最可靠的原始科学论文。读者对象： 1.任何从事与化学合成、药物合成、精细化工相关专业的科研人员、企业管理人员。 2.有机化学专业、药学专业、生物制药专业等大专院校的高年级学生、研究生、教师及科研人员。 3.从事客户委托的药物原料与药物中间体合成的科研人员、企业管理人员。编辑推荐对于制药企业而言,一个好的药物全合成路线, 可以大大缩短生产周期,简化生产工艺,降低生产成本,节约能源,减少或消除对环境的化学污染与排放。本书为了顺应我国近年来生物制药及医药工业飞速发展的潮流编写的，详细介绍了近五年美国FDA批准上市的所有（109个）新分子实体药的化学全合成路线。这些全合成路线多数是国外制药厂目前正在使用的工艺，其经济效益及社会效益都是极为显著，因此本书既有较高的科学价值又有很大的实用性。作者简介陈清奇，旅美药学家和化学家，担任美国MedKoo生物医药科研公司总裁，同时兼任美国数家生物制药公司的技术顾问，中国国内数个大学的客座教授。研究领域为药物化学，纳米医学体外诊断技术。书籍目录 Abiraterone Acetate（醋酸阿比特龙）001 Aclidinium Bromide（阿克利溴铵）006 Afatinib（阿法替尼）009 Alcaftadine（阿卡他定）014 Alogliptin（阿格列汀）017 Apixaban（阿哌沙班）022 Apremilast（阿普斯特）028 Avanafil（阿伐那非）033 Axitinib（阿西替尼）038 Azilsartan Kamedoxomil（阿齐沙坦酯钾盐）044 Bazedoxifene（巴多昔芬）048 Bedaquiline（贝达喹啉）053 Belinostat（贝利司他）060 Boceprevir（波西普韦）064 Bosutinib（博舒替尼）071 Cabozantinib（卡博替尼）075 Canagliflozin（卡格列净）078 Carfilzomib（卡非佐米）083 Ceftaroline Fosamil（头孢洛林酯）087 Ceftolozane（噻呋特啰嗪）094 Ceritinib（色瑞替尼）098 Clobazam（氯巴占）101 Cobicistat（可比司他）104 Crizotinib（克里唑蒂尼）112 Dabigatran Etexilate Mesylate（甲磺酸达比加群酯）118 Dabrafenib（达拉菲尼）123 Dapagliflozin（达格列净）127 Dasabuvir（达沙布韦）132 Deferiprone（去铁酮）136 Dienogest（地诺孕素）138 Dolutegravir（度鲁特韦）141 Droxidopa（屈昔多巴）145 Efinaconazole（艾氟康唑）149 Eliglustat（依利格鲁司特）152 Elvitegravir（埃替格韦）155 Empagliflozin（依帕列净）161 Enzalutamide（恩杂鲁胺）166 Eribulin Mesylate（甲磺酸艾日布林）168 Eslicarbazepine Acetate（艾利西平醋酸酯）175 Estradiol Valerate（雌二醇戊酸酯）180 Ezogabine（依佐加滨）185 Finafloxacin（非那沙星）193 Fingolimod Hydrochloride（盐酸芬戈莫德）197 Florbetapir F 18（氟比他匹）205 Flutemetamol F 18（富特米他）211 Gabapentin Enacarbil（加巴喷丁恩那卡比）214 Gadobutrol（钆布醇）218 Gadoterate Meglumine（钆特酸葡甲胺）224 Ibrutinib（依鲁替尼）227 Icatibant（艾替班特）232 Idelalisib（艾代拉里斯）234 Indacaterol （茚达特罗）236 Ingenol Mebutate（巨大戟醇甲基丁烯酸酯）240 Ioflupane 123I（碘[123I]氟潘）242 Ivacaftor（依瓦卡特）247 Ledipasvir（雷迪帕韦）250 Linaclotide（利那洛肽）259 Linagliptin（利拉利汀）261 Lomitapide（洛美他派）267 Lorcaserin（氯卡色林）270 Lucinactant（芦西纳坦）274 Luliconazole（卢立康唑）276 Lurasidone（鲁拉西酮）279 Macitentan（马西替坦）283 Miltefosine（米替福新）286 Mipomersen Sodium（米泊美生钠）290 Mirabegron（米拉贝隆）292 Naloxegol（纳罗克格）296 Netupitant（奈妥吡坦）299 Nintedanib（尼达尼布）303 Olaparib（奥拉帕尼）307 Olodaterol（奥达特罗）311 Omacetaxine Mepesuccinate（高三尖杉酯碱）315 Ombitasvir（艾姆伯韦）319 Ospemifene（奥培米芬）323 Paritaprevir（帕瑞它韦）327 Pasireotide（帕瑞肽）331 Peramivir（帕拉米韦）333 Perampanel（吡仑帕奈）337 Pirfenidone（吡非尼酮）343 Pomalidomide（泊马度胺）345 Ponatinib（泊那替尼）351 Regorafenib（瑞戈非尼）355 Rilpivirine（利匹韦林）357 Riociguat（利奥西呱）366 Rivaroxaban（利伐沙班）370 Roflumilast（罗氟司特）378 Ruxolitinib（鲁索替尼）384 Simeprevir（司美匹韦）388 Sofosbuvir（索非布韦）396 Suvorexant（苏沃雷生）401 Tafluprost（他氟前列腺素）405 Tasimelteon（他司美琼）409 Tavaborole（它瓦波罗）413 Tedizolid Phosphate（磷酸特地唑胺）415 Telaprevir（替拉瑞韦）418 Teriflunomide（特立氟胺）426 Ticagrelor（替格瑞洛）430 Tofacitinib（托法替尼）438 Trametinib（曲美替尼）443 Umeclidinium（芜地溴铵）447 Vandetanib（凡德他尼）450 Vemurafenib（威罗菲尼）456 Vilanterol（维兰特罗）460 Vilazodone Hydrochloride（盐酸维拉佐酮）463 Vismodegib（维莫德吉）468 Vorapaxar（沃拉帕沙）470 Vortioxetine（沃替西汀）473 附录1本书使用的期刊名称缩写表477 附录2专利文献代码481 附录3美国药品专利中的用途代码定义484 附录4美国药品市场独占权代码定义530 附录5美国FDA于2010—2014批准上市的药物名单563 英文索引607 中文索引611 CAS登记号索引613 下载方式现在，这份资料分享给大家。小编在公众号设置了自动回复功能，在公众号后台回复关键词：新药全合成 ●书籍分享||有机氧化反应原理与应用 ●书籍分享||有机卤化反应原理及应用 ●推荐合成书籍【有机缩合反应原理与应用】 ●推荐合成书籍【有机环合反应原理与应用】 ●书籍分享||有机还原反应原理与应用 ●ChemDraw使用让你从化学菜鸟变成老鸟 ●干货分享||有机合成: 策略与控制 ●干货分享||有机合成工艺研发-副反应抑制法 ●基础有机化学(邢其毅)第3、4版教材+习题解析 ●ChemDrawV20最新版详细安装图文教程 ●干货分享||核磁共振二维谱 ●书籍分享||全合成中的经典:更多的目标、战略和方法 ●书籍分享||实用药物化学 ●书籍分享||基于模仿创新的小分子药物发明 ●书籍分享||制药工艺开发-目前的化学与工程挑战 ●书籍分享||手性合成:不对称反应及其应用(第5版) ●书籍分享||新药研发案例研究--明星药物如何从实验室走向市场 ●书籍分享||英汉·汉英化学化工词汇 ●书籍分享||有机化学结构与功能（第四版） ●书籍分享||过渡金属有机化学(原著第6版） ●重磅书籍分享||不对称催化基础 ●书籍分享||药物设计学-唐赟

上市批准高管变更

2024-03-21

·BiG生物创新社

全球最畅销的十款小分子药物！

作者｜betaloc小分子药物已过时？显然没有！随着抗体、基因疗法、细胞疗法等新兴药物模式的兴起，小分子药物一度被认为即将过时，事实上，小分子药物仍有其不可替代性，相对生物制剂来说，小分子在生产制造、运输、患者依从性、可用靶点范围、免疫原性等方面仍具有明显优势。在全球范围内的上市药物中，小分子药物的占比仍然高达近90%。而在2023年前三季度FDA批准的40个新药中，也有21个小分子。下面就让我们一起盘点小分子药物中的优等生，看看在销售榜单中的top 10都有哪些明星分子。根据Arizona大学Jon Njardarson课题组的统计，2022年前十大销售额的小分子药物总计销售超966亿美元，治疗领域涵盖病毒感染、心血管、肿瘤等。从公司来看，辉瑞不愧为小分子药物开发先驱，共有4款药物入围前十，其次是BMS，有阿哌沙班、来那度胺两款小分子药进入前十，合计贡献217亿美元营收。表1, 2022销售额 top 10小分子药物 01 奈玛特韦（Paxlovid，Nirmatrelvir）由辉瑞研发的一款3CL蛋白酶抑制剂，可以抑制3CL蛋白酶的作用，从而阻止新冠病毒后续的一系列复制活动。在临床试验中，Paxlovid可将新冠肺炎非住院患者的住院或死亡率降低89%。该药于2021年12月成为首款获得FDA紧急批准的新冠口服药，上市第一年，销售额便达到了189亿美元，一举超越阿哌沙班成为最畅销小分子药物。奈玛特韦是在先前开发的针对非典（SARS）的特效药PF-00835231基础上改造得来，辉瑞的研究人员发现，PF-00835231与SARS-CoV的结合位点，同样存在于新冠病原SARS-CoV-2，这意味着PF-00835231也许对新冠病毒同样有效，经测试证明确实如此，但静脉注射剂型太过繁琐，辉瑞便对PF-00835231进行结构优化并引入三氟乙酰胺基团，提高了生物利用度，使其可通过口服吸收。图1，由SARS特效药改造得到SARS-CoV-2特效药Paxlovid 02 阿哌沙班（Eliquis，apixaban）由BMS和辉瑞公司联合研发的一种新型凝血因子Xa（Factor Xa）抑制剂，分别于2011和2012年在欧洲和美国上市，用于患者术后静脉血栓栓塞症（VTE）预防及房颤患者脑卒中预防。虽然专利还未到期（2026年），但2022年销售额同比2021年仍降低了约30%，为117亿美元。阿哌沙班由BMS经过高通量筛选优化得到，对人FXa的Ki 0.08 nM，对 FXa 的选择性比其他人凝血蛋白酶高 30000 倍以上。与维生素K拮抗剂华法林等相比，阿哌沙班具有疗效更好，安全性更高的特点。图2, 阿哌沙班的结构优化过程 03 必妥维（Biktarvy）由吉利德科学公司研发，于2018年获FDA批准上市的用于治疗HIV的三合一复方新药，含有比克替拉韦（bictegravir）50mg/恩曲他滨（emtricitabine）200mg/丙酚替诺福韦（tenofovir alafenamide）25mg，bictegravir是HIV-1整合酶抑制剂，emtricitabine和tenofovir alafenamide都是核苷类似物，用作逆转录酶抑制剂。2020/2021/2022年的销售额分别为72.59亿、86.24亿、103亿美元，放量十分迅速。恩曲他滨和丙酚替诺福韦在2003和2015年就已经上市，只有比克替拉韦为Biktarvy复方新药中的NME成分，其化学结构与多替拉韦（Dolutegravir， GSK开发的HIV药物）类似，同为整合酶抑制剂，但Biktarvy安全性更佳。图3, Bictegravir（BIC）和Dolutegravir（DTG） 04 来那度胺（Revlimid, Lenalidomide）来那度胺由新基制药开发，是老药新用的经典案例，前身是臭名昭著的“反应停“沙利度胺。上世纪90年代，科学家发现沙利度胺有抗癌疗效，对其进行分子改造后得到来那度胺，后者于2005年获批上市，用于治疗多发性骨髓瘤（MM）、骨髓瘤增生异常综合征（MDS）等疾病。该药2020/2021/2022年的销售额分别为121亿、129亿、100亿美元，2023年进一步降至61亿美元，但上市至今累计销售额已达1050亿美元。图4, 沙利度胺与来那度胺后来，经过更广泛的研究，科学家发现来那度胺是通过分子胶水的机制诱导E3连接酶Cereblon (CRBN) 降解靶蛋白来发挥治疗作用，由此开发出了一项全新的小分子药物技术—蛋白水解靶向嵌合体（PROTAC），其能够弥补传统小分子药物难以靶向不可成药靶点的缺陷，诱导致病蛋白的降解。 05 恩格列净（Jardiance, Empagliflozin）由勃林格殷格翰公司研发的钠-葡萄糖协同转运蛋白-2 (SGLT2)抑制剂，于2014年8月获FDA批准上市，用于控制2型糖尿病成人患者的血糖和降低患者的心血管风险。SGLT2主要在肾脏表达，负责从肾小管腔重吸收过滤后的葡萄糖和钠，当SGLT2被抑制后，肾脏对葡萄糖和钠的重吸收都会减少，降低体内血糖浓度。该药2020/2021/2022年销售额为41.08亿、58.29亿、82.15亿美元。图5, 恩格列净作用机制 06 伊布替尼（Imbruvica，Ibrutinib）该药于2013年在美国上市，是全球首个BTK共价抑制剂，用于治疗套细胞淋巴瘤（MCL）、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）和华氏巨球蛋白血症（WM）等血液肿瘤。然而，伊布替尼作为一代抑制剂，对BTK选择性不够好，存在脱靶效应，并可能抑制其他具有相同保守的Cys残基的激酶从而导致过敏和腹泻等不良反应。图6, 已上市的BTK抑制剂结构该药2020/2021/2022年销售额为94.42亿、97.77亿、83亿美元，核心专利将于2026年到期，但由于泽布替尼和其他后来者的强力竞争，伊布替尼的市场急剧下滑，2023年销售额仅为36亿美元。而2022年刚获FDA批准的泽布替尼，2023年销售额已达到13亿美元。 07 多替拉韦（Tivicay，Dolutegravir）由GSK和ViiV Healthcare共同研发，与bictegravir一样，是HIV整合酶抑制剂，阻断HIV病毒DNA整合来限制HIV的复制，于2013年8月获FDA批准上市。多替拉韦还是GSK其他三款HIV产品——Triumeq(多替拉韦/阿巴卡韦/拉米夫定)、Juluca(多替拉韦/利匹韦林）和Dovato（多替拉韦/拉米夫定)的成分之一，该药2022年销售额达到了81亿美元。在dolutegravir之前，已经有raltegravir、elvitegravir等整合酶抑制剂上市，对整合酶药物结合口袋的构效关系研究也已经比较清楚，于是盐野义和GSK的研究人员在总结前期发表的分子结构基础上引入氧原子设计了化合物5，以增强化何物对整合酶的结合能力，之后又对生物利用度、半衰期和突变体结合活性进行了优化，得到了dolutegravir，半衰期为6 h，生物利用度达到了34%。图7, Dolutegravir（3）结构优化历程 08 Trikafta (Elexacaftor, Tezacaftor, Ivacaftor)由福泰制药研发，于2019年10月获FDA批准上市，用于治疗6岁及以上囊性纤维化跨膜电导调节蛋白（CFTR）的基因至少有一个F508del突变或其它有效突变的囊性纤维化（cystic fibrosis, CF）患者。Trikafta由三个小分子复方组成，他们同时结合致病的CFTR突变蛋白，彼此之间有协同作用，elexacaftor是新一代CFTR蛋白校正剂，帮助恢复携带F508del突变的CFTR蛋白的功能；tezacaftor帮助组装和运输CFTR蛋白至细胞表面来增强它的功能，ivacaftor则通过增加位于细胞表面CFTR通道的开放率（门控通道），提高CFTR蛋白的活性，增加氯化物的转运。三种分子联合应用能增加CFTR蛋白的数量并增强蛋白的功能。图8，Trikafta含有的三个小分子结构及其作用机制囊性纤维化是一种遗传性疾病，由CFTR的基因突变引起，在美国有3万多名囊性纤维化患者，全世界约有7万名患者。Trikafta则是福泰制药的当家产品，该药在2020/2021/2022/2023年销售额分别为39亿、57亿、76亿、89亿美元，年均增长率达32%，在2023年更是贡献了福泰全年总营收的90%。 09 利伐沙班（Xarelto，Rivaroxaban）利伐沙班由拜耳制药开发，为首个上市的Factor Xa抑制剂（分别于2008和2011年在欧洲和美国获批），它通过抑制因子Xa可以中断凝血瀑布的内源性和外源性途径，抑制凝血酶的产生和血栓形成。Bayer于1998年便启动了直接抑制FXa小分子抗凝药物研发项目，经过高通量筛选20万化合物后得到了一个IC50为70 nM、选择性抑制FXa体外酶活的苗头化合物，并对其进行结构优化以提升抑制活性和口服生物利用度，最终优化得到含有吡咯烷酮结构的利伐沙班，IC50为0.7 nM，口服生物利用度接近60%。图9，利伐沙班抗凝血机制 10 恩杂鲁胺（Xtandi, Enzalutamide）由美国Medivation公司研发，是一款成功的me-better的非甾体雄激素受体（androgen receptor，AR）抑制剂，于2012年获FDA批准上市，用于治疗去势性前列腺癌和转移性激素敏感性前列腺癌。最初的药化工作是由UCLA大学的Jung和Memorial Sloan-Kattering癌症中心的Sawyers合作进行, Jung等以药物尼鲁米特和雄激素激动剂RU59063为出发点, 试图优化得到AR拮抗剂，最终从合成的200多个化合物中优选出恩杂鲁胺。图10 恩杂鲁胺及其先导化合物结构恩杂鲁胺2020/2021/2022年销售额51亿、56.36、62亿，销售额仍处于稳定爬坡中。Ref：Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis. 2011 May;31(4):478-92.Owen DR, Allerton CMN, Zhu Y. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science. 2021 Dec 24;374(6575):1586-1593.Liu J, Chen C, Wang D, Zhang J, Zhang T. Emerging small-molecule inhibitors of the Bruton's tyrosine kinase (BTK): Current development. Eur J Med Chem. 2021 May 5;217:113329.Perzborn, E., Roehrig, S., Straub, A.et al. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov 10, 61–75 (2011).https://www.xareltohcp.com/Fiedorczuk K, Chen J. Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators. Science. 2022 Oct 21;378(6617):284-290.Yoshiyuki Taoda, Shuichi Sugiyama & Takahiro Seki. (2023) New designs for HIV-1 integrase inhibitors: a patent review (2018-present). Expert Opinion on Therapeutic Patents 33:1, pages 51-66.共建Biomedical创新生态圈！如何加入BiG会员？

上市批准专利到期细胞疗法基因疗法

2023-12-05

·SYNAPSE

What are HIV-1 integrase inhibitors and how do you quickly get the latest development progress?

HIV-1 integrase is an enzyme that plays a crucial role in the replication of the human immunodeficiency virus (HIV-1) within the human body. It is responsible for the integration of viral DNA into the host cell's genome, allowing the virus to establish a persistent infection. By catalyzing the integration process, HIV-1 integrase enables the virus to evade the immune system and replicate efficiently. Understanding the function of this enzyme has led to the development of integrase inhibitors, a class of antiretroviral drugs that target HIV-1 integrase and effectively suppress viral replication, helping to manage HIV infection and prevent the progression to acquired immunodeficiency syndrome (AIDS). Antiretroviral therapy (ART) is the most important measure in the treatment of AIDS. With the widespread clinical application of ART, HIV drug resistance has become a significant factor affecting therapeutic efficacy. HIV-1 integrase inhibitors, a new target of action, have attracted widespread attention since their launch due to their high efficiency and low toxicity. They have become the first choice recommendation in many international AIDS treatment guidelines. Based on the analysis of the data provided, GSK Plc, Gilead Sciences, Inc., and Merck & Co., Inc. are the companies growing fastest under the target HIV-1 integrase. The highest stage of development for this target is the approved stage, with drugs approved for the indication of HIV Infections. Small molecule drugs are progressing most rapidly under this target, indicating intense competition around innovative drugs. The United States, European Union, and Japan are the countries developing fastest under this target, with China showing significant progress. Overall, the current competitive landscape for the target HIV-1 integrase is promising, with potential for future development and advancements in the field. The mechanism of action of HIV-1 integrase inhibitorsHIV-1 integrase inhibitors are a class of drugs used in the treatment of HIV/AIDS. HIV-1 integrase is an enzyme that plays a crucial role in the replication of the human immunodeficiency virus (HIV). It is responsible for inserting the viral DNA into the DNA of the host cell, allowing the virus to integrate and establish a persistent infection. Integrase inhibitors work by blocking the activity of the HIV-1 integrase enzyme, preventing the integration of viral DNA into the host cell's DNA. This inhibits the replication of the virus and helps to control the progression of HIV/AIDS. These inhibitors are typically used in combination with other antiretroviral drugs as part of highly active antiretroviral therapy (HAART). By targeting different stages of the HIV life cycle, combination therapy can effectively suppress viral replication, reduce the viral load, and improve immune function. Some examples of HIV-1 integrase inhibitors include raltegravir, elvitegravir, dolutegravir, and bictegravir. These drugs are usually taken orally and are well-tolerated, with common side effects including headache, nausea, and diarrhea. Regular monitoring of viral load and CD4 cell count is essential to assess treatment effectiveness and adjust the therapy if needed. It is important to note that HIV-1 integrase inhibitors are specifically designed to target the HIV-1 integrase enzyme and are not effective against other types of integrase or unrelated viruses. Additionally, like all antiretroviral drugs, they do not cure HIV/AIDS but can significantly improve the quality of life and increase the lifespan of individuals living with the disease. Catalog of HIV-1 integrase InhibitorsThe currently marketed HIV-1 integrase inhibitors include: Cabotegravir sodiumCabotegravir/RilpivirineDolutegravir Sodium/LamivudineBictegravir/Emtricitabine/Tenofovir Alafenamide FumarateCobicistat/Elvitegravir/Emtricitabine/Tenofovir Alafenamide FumarateAbacavir sulfate/Dolutegravir sodium/LamivudineDolutegravir SodiumCobicistat/Elvitegravir/Emtricitabine/Tenofovir Disoproxil FumarateRaltegravir PotassiumDolutegravir/Lamivudine/Tenofovir Disoproxil FumarateFor more information, please click on the image below. What is the purpose of using HIV-1 integrase inhibitors?HIV-1 integrase inhibitors are a class of antiretroviral drugs used in the treatment of HIV/AIDS. For more information, please click on the image below to log in and search. How can I get the most recent advancements in HIV-1 integrase inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of HIV-1 integrase inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

100 项与埃替格韦相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06677	埃替格韦	J05AX11	DB09101

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
HIV感染	欧盟	Gilead Sciences, Inc.	2013-11-13
HIV感染	冰岛	Gilead Sciences, Inc.	2013-11-13
HIV感染	列支敦士登	Gilead Sciences, Inc.	2013-11-13
HIV感染	挪威	Gilead Sciences, Inc.	2013-11-13

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
获得性免疫缺陷综合征	临床3期	美国	Gilead Sciences, Inc.	2013-08-26
获得性免疫缺陷综合征	临床3期	意大利	Gilead Sciences, Inc.	2013-08-26
获得性免疫缺陷综合征	临床3期	南非	Gilead Sciences, Inc.	2013-08-26
获得性免疫缺陷综合征	临床3期	西班牙	Gilead Sciences, Inc.	2013-08-26
获得性免疫缺陷综合征	临床3期	泰国	Gilead Sciences, Inc.	2013-08-26
获得性免疫缺陷综合征	临床3期	乌干达	Gilead Sciences, Inc.	2013-08-26

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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


NCT01923311 (CTgov)	临床2/3期	获得性免疫缺陷综合征	31	ATV/r+LPV/r+EVG (Age 6 to < 12 Years)	齋簾鹽窪蓋範廠觸醖獵(襯鬱襯夢壓遞獵鹹築艱) = 獵鹽製鹽膚鏇顧鹽製廠築積範壓蓋窪鏇網繭遞 (製壓廠觸淵遞繭構網觸, 7302.44) 更多	-	2018-07-11
				FPV/r+ATV/r+LPV/r+DRV/r+EVG+TPV/r (Age 6 to < 18 Years With Screening HIV-1 RNA > 1000 Copies/mL)	糧鹽糧積選蓋糧鑰蓋鬱 = 構夢窪淵餘築餘憲構淵鑰網選觸網齋範鹽夢艱 (鹹鹽願鑰範築鑰窪觸鬱, 願製壓糧鑰鏇顧窪艱選 ~ 醖觸觸蓋選膚壓淵積襯) 更多
IAS2018	N/A	-	-	Switch to E/C/F/TAF	獵獵鏇鏇餘顧蓋遞繭糧(顧糧壓憲齋顧夢遞艱淵) = 築願淵觸夢餘廠積壓憲鬱鏇壓鬱膚遞壓築鑰遞 (構積餘鬱遞憲廠鹽醖鑰 ) 更多	-	2018-01-01
				Continue ABR	獵獵鏇鏇餘顧蓋遞繭糧(顧糧壓憲齋顧夢遞艱淵) = 鬱襯窪鬱鹹醖顧衊獵餘鬱鏇壓鬱膚遞壓築鑰遞 (構積餘鬱遞憲廠鹽醖鑰 ) 更多
IAS2017	N/A	HIV感染	33	Elvitegravir	範網積廠鹹築遞製蓋憲(選艱餘窪築繭鹹餘鏇繭) = 製選膚選鏇觸遞積構獵鏇夢簾鬱獵鹽襯範艱餘 (糧構齋蓋積壓餘鬱壓壓 ) 更多	-	2017-01-01
				Cobicistat	範網積廠鹹築遞製蓋憲(選艱餘窪築繭鹹餘鏇繭) = 淵憲鬱膚鹽壓蓋繭鹹鑰鏇夢簾鬱獵鹽襯範艱餘 (糧構齋蓋積壓餘鬱壓壓 ) 更多
IAS2017	N/A	HIV感染	75	Elvitegravir-based STR	繭艱憲廠蓋鑰蓋網憲夢(簾觸淵憲選壓鏇齋鹹糧) = 壓蓋壓構繭壓網顧蓋製鹹願膚網選壓窪壓齋積 (夢廠觸鏇網壓夢窪膚鹽 )	-	2017-01-01
				Dolutegravir-based STR	繭艱憲廠蓋鑰蓋網憲夢(簾觸淵憲選壓鏇齋鹹糧) = 構餘遞選選襯廠齋範鹹鹹願膚網選壓窪壓齋積 (夢廠觸鏇網壓夢窪膚鹽 )
NCT00445146 (CTgov)	临床2期	HIV感染	192	ARV regimen+RTV+EVG	鑰艱廠衊選艱糧糧顧築 = 構築築獵積選鹽鬱繭膚鏇顧衊淵憲範繭選繭壓 (鏇積襯鹹鹽糧鹽淵築鏇, 鏇顧觸艱製鏇遞餘蓋夢 ~ 糧窪襯鑰壓範觸繭網壓) 更多	-	2016-04-25
WAVES Study (IAS2015)	N/A	HIV感染	575	Elvitegravir (EVG) / cobicistat (COBI) / emtricitabine (FTC)/ tenofovir disoproxil fumarate (TDF)	積鬱鏇簾鬱遞蓋淵獵積(醖製積憲衊獵膚網窪餘) = 網鹽觸構糧膚糧餘窪鏇鏇鬱艱鹹膚鑰網鬱艱壓 (獵鹹鹽鏇糧繭遞築鏇觸 )	积极	2015-01-01
				ritonavir (RTV) boosted atazanavir (ATV) plus FTC/TDF	積鬱鏇簾鬱遞蓋淵獵積(醖製積憲衊獵膚網窪餘) = 積積築齋鏇獵衊範鏇憲鏇鬱艱鹹膚鑰網鬱艱壓 (獵鹹鹽鏇糧繭遞築鏇觸 )
NCT00708162 (CTgov)	临床3期	HIV感染	724	Background regimen+Elvitegravir (Elvitegravir)	鏇繭壓鹽鏇艱鹽憲窪鏇 = 鑰繭顧窪製窪壓膚範鬱觸選憲齋遞鏇鏇鑰淵廠 (艱鬱蓋鑰夢衊遞觸膚糧, 簾餘鹽淵餘餘鏇蓋糧繭 ~ 襯壓鹹襯鏇鏇夢艱簾遞) 更多	-	2014-11-06
				Background regimen+raltegravir (Raltegravir)	鏇繭壓鹽鏇艱鹽憲窪鏇 = 鹹鬱鏇襯構衊壓廠廠顧觸選憲齋遞鏇鏇鑰淵廠 (艱鬱蓋鑰夢衊遞觸膚糧, 齋鹹範窪壓衊選醖艱簾 ~ 艱選鹽範選鹹夢醖顧艱) 更多
IAS2013	N/A	-	1,408	Elvitegravir/cobicistat/emtricitabine/tenofovir DF	鏇願鹽簾繭齋築衊蓋遞(網鏇淵壓鹽製繭憲齋醖) = Rates of AEs leading to study drug discontinuation were similar in the 3 groups (5% vs 7% vs 6%) 鏇壓襯構憲餘夢蓋鹽築 (製簾夢獵鬱範糧壓膚範 ) 更多	-	2013-01-01
				Efavirenz/emtricitabine/tenofovir DF
IAS2013	N/A	-	-	Elvitegravir/cobicistat/emtricitabine/tenofovir DF	鏇艱範鏇顧獵獵鹹膚鬱(膚鹽艱繭憲夢選憲壓鏇) = 觸觸願鏇餘糧齋糧構夢構窪鬱鬱願鹹獵壓餘齋 (鹽願繭齋壓糧齋糧鏇壓 )	积极	2013-01-01
				Efavirenz/emtricitabine/tenofovir DF	鏇艱範鏇顧獵獵鹹膚鬱(膚鹽艱繭憲夢選憲壓鏇) = 選膚鑰觸願糧選積範淵構窪鬱鬱願鹹獵壓餘齋 (鹽願繭齋壓糧齋糧鏇壓 )
Study 118 (IAS2013)	N/A	肾功能不全 \| HIV感染	106	Elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB)	獵構衊觸鏇鑰膚願積膚(壓艱壓淵構鑰簾壓齋製) = 膚觸蓋鬱齋積製鏇顧顧糧鏇淵窪餘齋淵範願鹹 (顧鑰鬱觸積艱鹹醖繭夢 )	-	2013-01-01
				Cobicistat-boosted protease inhibitor regimens	獵構衊觸鏇鑰膚願積膚(壓艱壓淵構鑰簾壓齋製) = 築鹹網顧積襯鏇襯簾壓糧鏇淵窪餘齋淵範願鹹 (顧鑰鬱觸積艱鹹醖繭夢 )