更新于：2024-04-01

SGLT2

钠-葡萄糖协同转运蛋白-2

更新于：2024-04-01

基本信息

别名

钠葡糖转运子2、Low affinity sodium-glucose cotransporter、Na(+)/glucose cotransporter 2

+ [5]

简介

Electrogenic Na(+)-coupled sugar simporter that actively transports D-glucose at the plasma membrane, with a Na(+) to sugar coupling ratio of 1:1. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump (PubMed:20980548, PubMed:28592437, PubMed:34880493). Has a primary role in D-glucose reabsorption from glomerular filtrate across the brush border of the early proximal tubules of the kidney (By similarity).

关联

项与 SGLT2 相关的药物

Janagliflozin

脯氨酸加格列净

靶点

SGLT2

作用机制

SGLT2抑制剂

在研机构

惠升生物制药股份有限公司

原研机构

山东轩竹医药科技有限公司

在研适应症

2型糖尿病

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

中国

首次获批日期2024-01-16

Henagliflozein Proline/Metformin Hydrochloride

恒格列净/二甲双胍

靶点

PRKAB1 x SGLT2

作用机制

PRKAB1激活剂 [+1]

在研机构

山东盛迪医药有限公司初创企业

原研机构

山东盛迪医药有限公司初创企业

在研适应症

2型糖尿病

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

中国

首次获批日期2023-12-29

Enavogliflozin/METFORMIN HYDROCHLORIDE

靶点

PRKAB1 x SGLT2

作用机制

PRKAB1激活剂 [+1]

在研机构

Daewoong Pharmaceutical Co., Ltd.

原研机构

Daewoong Pharmaceutical Co., Ltd.

在研适应症

2型糖尿病

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

韩国

首次获批日期2023-06-14

2,388

项与 SGLT2 相关的临床试验

NCT04818034 / Recruiting临床2期IIT

The Effect of Sodium-glucose Cotransporter (SGLT) 2 Inhibitors on Cystine Stone Formation: A Preliminary Study

Cystinuria is an inherited autosomal recessive disorder of the kidney that is the result of an inability to reabsorb cystine from the urine. Supersaturation of cystine in the urine produces crystals that precipitate and form stones in the kidney, which can be a cause of obstruction, infection, and chronic kidney disease. Cystine stones constitute a major health challenge for affected individuals with cystinuria because of the frequent recurrence of painful symptoms and the current absence of effective, patient-accepting treatment.
A mainstay of therapy is breaking or preventing the cystine bond on the molecular level such that cystine (which is formed from the joining of two cysteine amino acids and their corresponding sulfur atoms) cannot precipitate in the urine. It is hypothesized that a glucose molecule may be able to do this if introduced into the urine. SGLT-2 inhibitors are a class of drug that are FDA approved to treat diabetes mellitus (DM) and heart failure by inhibiting an enzyme in the kidney that allows for reabsorption of glucose from the urine. This effectively increases the concentration of glucose in the urine. Our hypothesis suggests that administration of this drug to patients with cystine will introduce sufficient glucose into the urine to prevent the formation of cystine stones. To date, there has been no published data on the effectiveness of this therapy for this indication, although the dosage and administration would be identical to that already approved by the FDA for the treatment of DM and heart failure.

开始日期2025-05-02

申办/合作机构

The University of California, San Francisco

NCT05885074 / Not yet recruiting临床2期IIT

Mechanistic Insights to Weight Loss Maintenance Through SGLT2 Inhibitors

Obesity increases the risk of cardiometabolic diseases such as hypertension and diabetes. Weight loss interventions such as low-calorie diet and physical activity are effective for weight loss in the short term, but weight loss maintenance (WLM) with low-calorie diet and physical activity is challenging. Weight loss is associated with a reduction in the amount of calories needed to maintain the body at rest, called the resting energy expenditure (REE), which may be a probable mechanism for this lack of WLM. Most individuals are unable to adequately change their diet and increase their physical activity levels to overcome this decrease in REE which prevents WLM. Therefore, techniques that increase REE may promote WLM in these individuals. Pre-clinical studies for Empagliflozin - Sodium-glucose Cotransporter-2 (SGLT2) inhibitor have shown an increase in REE. Thus, in addition to reducing the cardiovascular risk, SGLT2 inhibitor may promote WLM by increasing REE. This study aims to promote WLM in obese individuals by increasing the REE using SGLT2 inhibitor therapy.

开始日期2025-01-30

申办/合作机构

The University of Alabama at Birmingham

NCT06012266 / Not yet recruiting临床2期

Dose Rationale for Dapagliflozin and Empagliflozin in Paediatric Heart Failure: a Phase II.a Pharmacokinetics, Ease-of-swallow, Safety and Proof-of-concept Study Among Children 6-18 Years of Age

This study aims at exploring the use of Dapagliflozin and Empagliflozin in children and adolescents 6-18 years old with heart failure. These molecules are effective in reducing hospitalisations and mortality in adults with heart failure and are used in adolescents with type 2 diabetes mellitus, but little is known on children with heart failure. Particularly, the best dose to use in this population is currently unknown. This trial aims to:
1. define a dose rationale for this indication and age group (pharmacokinetic study),
2. assess and monitor safety,
3. assess ease-of-swallow,
4. explore middle-term (4-6 weeks) efficacy and efficacy markers.
Participants will be asked to attend 4 study visits over 4-6 weeks, and one end-study visit 2-12 weeks thereafter. Visits 1 and 3 will entail an 8h day-hospital stay, while Visits 2, 4 and the end-study visit will be outpatient clinics (approximately 2h). Participants will be asked to take the studied drug once daily during the 4-6 weeks of the study period.
All participants will take both Dapagliflozin and Empagliflozin: 6 will start with Dapagliflozin first (Visits 1-2) and then switch to Empagliflozin (Visits 3-4), while 6 will start with Empagliflozin first (Visits 1-2) and then switch to Dapagliflozin (Visits 3-4). No comparison group is foreseen for this study.

开始日期2024-08-01

申办/合作机构

Centre Hospitalier Universitaire Vaudois

[+2]

100 项与 SGLT2 相关的临床结果

登录后查看更多信息

100 项与 SGLT2 相关的转化医学

登录后查看更多信息

0 项与 SGLT2 相关的专利（医药）

登录后查看更多信息

2,746

项与 SGLT2 相关的文献（医药）

2024-03-01·American journal of preventive cardiology

Glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter 2 inhibitor use among adults with diabetes mellitus by cardiovascular-kidney disease risk: National Health and Nutrition Examination Surveys, 2015-2020.

Article

作者: Joshua A Jacobs ; Alexander R Zheutlin ; Catherine G Derington ; Jordan B King ; Ambarish Pandey ; Adam P Bress

Objective:

Glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) lower adverse cardiac and kidney events among high-risk patients with diabetes mellitus (DM) and are now guideline-recommended as first-line therapy alongside metformin. However, the adoption of these new treatments from 2015 to 2020 among the highest-risk adults with DM remains unclear.

Methods:

We performed a cross-sectional analysis of the National Health and Nutrition Examination Surveys (NHANES) 2015-2020 to estimate the use of GLP1-RAs and SGLT2Is among adults with DM overall and by level of cardiovascular and kidney risk (CKR). We defined high CKR by history of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), heart failure, or age ≥55 years with at least 2 ASCVD risk factors (i.e., obesity, hypertension, hyperlipidemia, or current smoker).

Results:

Overall, 2,432 participants with DM (mean age 60.6 years, 46.8 % female, 58.8 % Non-Hispanic White) were included, of which 1,869 and 563 were with and without high CKR, respectively. Participants with vs. without high CKR were more likely to be older, have higher systolic blood pressure, lower estimated glomerular filtration rate, use oral antidiabetic agents, and have health insurance. Overall, the weighted prevalence of GLP1-RA or SGLT2I was 9.0 % (95 % confidence interval [CI] 6.9-11.0): 4.8 % (95 % CI 3.6-6.1) took GLP1-RAs, and 5.1 % (95 % CI 3.3-7.0) took SGLT2Is. Use of GLP1-RAs or SGLT2Is did not differ between participants with vs. without high CKR (adjusted prevalence ratio [aPR] 1.00; 95 % CI 0.98-1.02). Participants with ASCVD were more likely to be on a GLP1-RA or SGLT2I (aPR 1.28; 95 % CI 1.25-1.31), while adults with CKD were less likely (aPR 0.84; 95 % CI 0.82-0.86).

Conclusion:

Among US adults with DM, GLP1-RA and SGLT2I use was low regardless of CKR. Data since 2020 analyzing the utilization of GLP1-RAs and SGLT2Is among high-CKR patients with DM is needed to identify implementation strategies for increased utilization.

2024-02-25·Clinical and experimental nephrology

Effects of sodium-glucose co-transporter 2 inhibitors on ultrafiltration in patients with peritoneal dialysis: a protocol for a randomized, double-blind, placebo-controlled, crossover trial (EMPOWERED).

Article

作者: Yohei Doi ; Maki Shinzawa ; Tetsuya Arisato ; Hideaki Oka ; Ayumi Matsumoto ; Harumi Kitamura ; Yumi Nakazono ; Yoichi Nishiya ; Yoshiyasu Ueda ; Taro Kamimura ; Terumasa Hayashi ; Fumiki Yoshihara ; Yoshitaka Isaka

BACKGROUND:

Volume overload is common and associated with high mortality in patients on peritoneal dialysis (PD). Traditional strategies including diuretics, water/salt restriction, and icodextrin-based solutions cannot always fully correct this condition, necessitating novel alternative strategies. Recent studies confirmed the expression of sodium-glucose cotransporter 2 (SGLT2) in the human peritoneum. Experimental data suggest that SGLT2 inhibitors decrease glucose absorption from the PD solution, thereby increasing the ultrafiltration volume. This trial aims to assess whether SGLT2 inhibitors increase the ultrafiltration volume in patients on PD.

METHODS:

The EMPOWERED trial (trial registration: jRCTs051230081) is a multicenter, randomized, double-blind, placebo-controlled, crossover trial. Patients with clinically diagnosed chronic heart failure are eligible regardless of the presence of diabetes if they use at least 3 L/day glucose-based PD solutions. Participants will be randomly assigned (1:1) to receive empagliflozin 10 mg once daily and then placebo or vice versa. Each treatment period will last 8 weeks with a 4-week washout period. This study will recruit at least 36 randomized participants. The primary endpoint is the change in the daily ultrafiltration volume from baseline to week 8 in each intervention period. The key secondary endpoints include changes in the biomarkers of drained PD solutions, renal residual function, and anemia-related parameters.

CONCLUSIONS:

This trial aims to assess the benefit of SGLT2 inhibitors in fluid management with a novel mechanism of action in patients on PD. It will also provide insights into the effects of SGLT2 inhibitors on solute transport across the peritoneal membrane and residual renal function.

2024-02-23·Diabetes

GRP78 contributes to the beneficial effects of SGLT2 inhibitor on proximal tubular cells in DKD.

Article

作者: Atsuko Nakatsuka ; Satoshi Yamaguchi ; Jun Wada

Beneficial effects of SGLT2 inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78 kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and Integrin ß1 beyond the chaperone property of GRP78. In STZinduced diabetic mouse kidneys, GRP78, SGLT2, and Integrin ß1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/Integrin ß1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained SERCA activity, promoted endoplasmic reticulum (ER) robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2 and Integrin ß1 and inhibited EMT and fibrosis in DKD. In non-diabetic CKD, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and contribute to tubular protection.

877

项与 SGLT2 相关的新闻（医药）

2024-03-30

·医药观澜

阿斯利康1类新药在华启动3期临床，针对难治性高血压

▎药明康德内容团队报道中国药物临床试验登记与信息公示网站近日公示，阿斯利康（AstraZeneca）已经在中国启动一项国际多中心（含中国）3期临床研究，旨在接受两种或两种以上药物治疗且未受控制的亚洲高血压受试者（包括难治性高血压受试者）中评估1类新药baxdrostat有效性和安全性。Baxdrostat是一种醛固酮合成酶抑制剂（ASI），最初由CinCor Pharma公司开发。2023年，阿斯利康通过收购CinCor Pharma公司获得了baxdrostat，以拓展其心肾疾病领域的在研产品管线。截图来源：中国药物临床试验登记与信息公示平台官网高血压是引起全球心血管疾病发病率和死亡率的主要原因之一。“难治性高血压”是指在改善生活方式基础上，联合使用三种不同类型降压药，每种药物都达到最大使用剂量，血压仍然无法达标，或是至少要使用≥4种药物才能达到降压目标的患者。数据显示，在高血压药物治疗的患者中，5%~30%的患者为难治性高血压，这类患者仍存在巨大的未满足医疗需求。研究显示，大约有20%的难治性高血压患者存在醛固酮升高，且这种升高与血压升高呈正相关，原因可能是醛固酮促进了水钠潴留、炎症、动脉硬化和氧化应激等，进一步促使难治性高血压形成。因此，十几年来，通过抑制醛固酮合酶来减少醛固酮的合成一直是高血压治疗的药物靶点。Baxdrostat（CIN-107）是一种新型的醛固酮合成酶抑制剂（ASI），其可选择性靶向由CYP11B2基因编码的醛固酮合成酶，同时对11ß-羟化酶（负责皮质醇合成的酶，由CYP11B1基因编码）的阻断活性的亲和力低得多。阿斯利康曾在此前发布的新闻稿中指出，baxdrostat代表了一种潜在领先的下一代ASI，因为它对醛固酮合成酶具有高度选择性，并保留了人体中的皮质醇途径。在临床前和1期研究中，baxdrostat对醛固酮合酶抑制显示出具有100:1的选择性，并且多个剂量水平的baxdrostat可降低血浆醛固酮水平，但不降低皮质醇水平。图片来源：123RF本次阿斯利康启动的是一项双盲、随机、安慰剂对照、多中心研究（BaxAsia研究）。本研究目的是在大约300例在基线时接受2种降压药或≥3种降压药稳定治疗方案，且年龄≥18岁的亚洲高血压受试者中评估1mg或2mg的Baxdrostat每天一次口服给药与安慰剂相比在降低收缩压（SBP）方面的安全性、耐受性和有效性。该研究中国主要研究者为上海交通大学医学院附属瑞金医院王继光主任医师。值得一提的是，2023年2月，研究人员在《新英格兰医学杂志》（NEJM）上发表了baxdrostat治疗难治性高血压患者的2期临床试验数据。研究结果显示：接受baxdrostat治疗的难治性高血压患者的血压出现了剂量相关的降低。除了针对难治性高血压，baxdrostat还有望用于治疗原发性醛固酮增多症（Spark-PA）以及慢性肾病（CKD）合并高血压患者，相关的2期或3期临床研究正在进行中。此外，该药也具有与阿斯利康的SGLT2抑制剂达格列净（dapagliflozin）联合用药的潜力，以进一步满足心脏肾脏疾病领域存在的高度未满足的医疗需求。参考资料：[1]中国药物临床试验登记与信息公示平台官网. Retrieved Mar 21, 2024. From http://www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml[2] Acquisition of CinCor Pharma complete. Retrieved 2023-02-24, from https://www.astrazeneca.com/media-centre/press-releases/2023/astrazeneca-acquires-cincor-for-cardiorenal-asset.html[3] Williams B. A New Dawn for Aldosterone as a Therapeutic Target in Hypertension.JAMA. Published online September 10, 2023. doi:10.1001/jama.2023.17087[4]Mason W. Freeman, Yuan-Di Halvorsen, et al.(2023)Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med.DOI: 10.1056/NEJMoa2213169本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转发授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文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。

临床2期临床3期临床结果并购临床成功

2024-03-28

·精准药物

最新报道的潜在成药分子

2024年2月，国外Biotech公司公布活性分子1. NivasorexantNivasorexant（ACT-539313）是 Actelion 公司生产的一种口服选择性 OX1 受体拮抗剂，是首个进入临床开发阶段的产品，最近完成了针对暴食症的概念验证 II 期临床试验。图片来源：February 2024 (drughunter.com)Jodi T. Williams等人报告了从双重奥曲肽受体拮抗剂开始的发现工作，并描述了一个偶然的发现引发的药物化学计划，最终确定了强效的 SO1RA ACT-539313。该化合物在大鼠日程表诱发的多尿症模型中的疗效支持了将其作为临床前候选药物的决定。对 DORA 系列进行先导化合物优化的过程中，研究者发现了一种结构修饰，这种修饰导致了从双重拮抗作用到 OX1 选择性拮抗作用的转变，原始吡咯烷系列的主要缺点，即在人类肝脏微粒体中的稳定性和 CYP3A4 抑制作用，也可以通过将中心环改为吗啉来解决。对 OX1 的效力、选择性和溶解性进行微调后，一些化合物被优先用于评估其在中枢神经系统中的分布。化合物 20（ACT-539313）成为最有希望进行体内研究的候选化合物。4-Acyl-3-triazolobenzylmorpholines 的 hOX1/OX2 IC50、选择性和人体微粒体稳定性在吗啉核心（20）的合成中，首先使用市售的 N-叔丁氧羰基-3-碘-二苯基丙氨酸，对其进行叔丁氧羰基脱保护，然后还原成相应的氨基醇。先用氯乙酰氯酰化，然后环化，得到吗啉酮 I-3。随后用 1,2,3-三唑进行芳基化、酰胺还原，再与所需的羧酸进行酰胺偶联，就得到了目标化合物。合成 4-酰基-3-苄基吗啉（20）基于可溶性和易于合成的考虑，化合物 20（ACT-539313）被优先用于药物开发。化合物 20（ACT-539313，nivasorexant）已经完成了 I 期临床试验，最近又完成了针对暴食症的 II 期临床试验，但未达到主要终点。2. ACT-1016-0707Cyrille Lescop等人发现新型、口服活性和选择性 LPA1 受体拮抗剂 ACT-1016-0707，可作为治疗纤维化疾病的临床前候选药物。图片来源：February 2024 (drughunter.com)ACT-1016-0707是来自 Idorsia 的一种强效口服活性 LPAR1 拮抗剂，在小鼠血管渗漏靶点接合模型中显示出疗效，被选定用于治疗纤维化疾病的临床前开发。值得注意的是，ACT-1016-0707 在结构上有别于之前公开的 LPAR1 拮抗剂，这可能有助于将其与其他因肝胆毒性问题而受阻的临床候选药物区分开来。哌啶 3 是一种强效、选择性溶血磷脂酸受体亚型 1 受体（LPAR1）拮抗剂，在小鼠皮肤血管渗漏靶点参与模型中显示出疗效。然而，化合物 3 与人体血浆蛋白结合率很高，在大鼠体内的清除率也很高，这可能会严重阻碍其临床开发。经过不断的先导优化，最终开发出了药效强、蛋白结合率低、代谢稳定、口服活性高的氮杂环丁烷 17。大鼠药代动力学（PK）研究显示，17 在肝脏中蓄积。体外研究表明，17 是有机阴离子共转运多肽 1B1 （OATP1B1）的底物。虽然类似物 24 不再是 OATP1B1 的底物，但 PK 研究表明该化合物会进行肠肝再循环。将羧酸侧链替换为非酸性的硫酰胺分子并进一步微调支架后，产生了强效、口服活性的 LPAR1 拮抗剂 49，并将其用于治疗纤维化疾病的临床前开发。从 Boc 保护的氮杂环丁烷-3-羧酸 73（方案 3）开始制备磺酰胺 48。在吡啶中用 POCl3 活化酸 73，然后与 6-氯-4-甲氧基吡啶-3-胺偶联，得到酰胺 96，产率中等。将溴吡啶分子与异丙烯基硼酸频哪醇酯进行铃木偶联，可以得到产率较高的烯烃 97。在 Pt2O 催化下，右侧吡啶上的异丙基被氢化，而左侧的 2-氯吡啶基没有被还原（98）。通过 Boc 脱保护，得到氮杂环丁烷 99，在碱存在下用硫酰胺处理 99，将其转化为所需的硫酰胺 48。同样，氮杂环丁烷 63与磺酰胺反应也可得到磺酰胺 49。制备氨基磺酸 48 和 49a体外数据表明，化合物 49 是一种强效、选择性 LPAR1 拮抗剂，在 LPA 诱导的皮肤血管渗漏小鼠模型中具有口服活性。基于上述特性，硫酰胺 49 被选为治疗纤维化疾病的临床前开发候选药物，目前正在进行首次人体试验研究。3. CT1812CT1812是Cognition Therapeutics 公司生产的一种具有口服活性和脑渗透性的 sigma-2 受体拮抗剂，目前正处于治疗阿尔茨海默病的 II 期临床7研究阶段。图片来源：February 2024 (drughunter.com)Gilbert M. Rishton等人开发了一种无偏见的表型神经元测定法来测量可溶性 Aβ 寡聚体的突触毒性效应。筛选了一系列通过条件提取法制备的中枢神经系统类药物小分子。发现了能防止和逆转神经元中 Aβ 寡聚体的突触毒性效应的化合物，首款口服小分子研究药物 7（CT1812）正在进行治疗阿尔茨海默病的研究。异吲哚啉抗 AβO 化合物的一般合成方法已经开发出来。通过钯介导的芳基碘化物 14 和 15与 2-甲基-3-丁炔-2-胺的偶联，得到了 gem-二甲基取代的丙炔胺 16 和 17（17 的收率为 74%），从而可以直接获得 gem-二甲基取代的异吲哚啉。这些化合物随后被氢化为中间胺 19 和 20（20 的产率为 100%）。现有的手性 α-甲基胺 12 和 18以及 gem-二甲基取代胺 19 和 20 与相应的双苄基溴 21-23 缩合，得到异吲哚啉抗 AβO 化合物 4-7（7 的收率为 63%）。制备异吲哚啉化合物 4-7化合物 7（CT1812）是口服治疗阿尔茨海默病的第一类小分子候选药物。与安慰剂相比，CT1812 能显著提高 AD 患者 CSF 中 Aβ 寡聚体的浓度，降低突触蛋白和磷酸化 tau 片段的浓度，并逆转 CSF 中许多表达失调的 AD 相关蛋白。4. AZD1390AZD1390 是AstraZeneca公司生产的一种强效、选择性共济失调毛细血管扩张症突变激酶（ATM）抑制剂，具有良好的临床前 PK 和 NHP PET 研究中显著的脑暴露，被选中用于临床开发，以探索 ATM 对颅内恶性肿瘤的放射增敏作用。图片来源：February 2024 (drughunter.com)从临床候选药物 AZD0156 （4 ）开始，Kurt G. Pike等人对咪唑喹啉-2-酮支架进行了研究，目的是改善其在人体中的中枢神经系统暴露。除了调节亲脂性，他们还探索了旨在减少氢键、碱性和分子灵活性的策略。这些研究发现化合物 24（AZD1390）是一种非常有效的 ATM 选择性抑制剂，具有良好的临床前药代动力学特征。化合物 24 作为临床候选药物被开发，以探索 ATM 对颅内恶性肿瘤的放射增敏作用。通过对咪唑并[4,5-c]喹啉-2-酮系列进行优化，在提高 BBB 穿透性的同时，保持了 4 所固有的出色药效、选择性和特性，最终确定了首个据报道适合临床开发的脑穿透性 ATM 抑制剂 24（AZD1390）。目前，AZD1390（24）正处于与放疗联合治疗颅内恶性肿瘤的 1 期临床研究中探索无环碱性取代基。碱性中心和芳香核心之间的四原子连接物（丙氧基）似乎是提高药效的最佳选择，在 24 号喹啉上引入一个氟后，化合物的各种性质达到了令人满意的平衡，符合我们的进展标准。无环碱性取代基的 SARa从6-溴-4-氯-7-氟喹啉-3-羧酸乙酯 37 开始，制备了一系列 7-氟喹啉类似物。溴化物 38 与 6-氟吡啶-3-基)硼酸反应生成中间体 39，中间体 39 随后与一系列环胺发生 SNAr 反应，生成化合物 12 和 16。O 键类似物（21 和 24）是39 与适当的醇（用氢化钠预处理以形成烷氧化物）进行处理而制备的。在这些情况下，对反应条件和亲核剂化学计量的控制足以防止喹啉的 C-7 氟发生位移。含碱性侧链的 7-氟-1,3-二氢-2H-咪唑并[4,5-c]喹啉-2-酮的合成5. TYA-108TYA-018 是 Tenaya Therapeutics 公司的一种临床前小分子 HDAC6 抑制剂，在射血分数保留型心力衰竭（HFpEF）雄性小鼠模型中显示出临床前疗效。值得注意的是，TYA-018 在与 SGLT2 抑制剂联用时显示出更强的疗效，治疗 HFpEF 的一个有前途的靶点。此外，TYA-018 还能抑制人心脏成纤维细胞的活化，增强心肌细胞的线粒体呼吸能力。图片来源：February 2024 (drughunter.com)中间体化合物3的合成目标化合物TYA-108的合成参考文献https://doi.org/10.1021/acs.jmedchem.3c01894https://doi.org/10.1021/acs.jmedchem.3c01827https://doi.org/10.1021/acsmedchemlett.1c00048https://doi.org/10.1021/acs.jmedchem.3c02277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↓

临床2期临床结果ASCO会议

2024-03-28

·Firstwordpharma

Steep markups on GLP-1s, insulin pens hinder diabetes care: study

Amid burgeoning global demand for effective diabetes medicines, including GLP-1 agonists like Novo Nordisk's Ozempic (semaglutide) and Eli Lilly's Trulicity (dulaglutide), a new study suggests these treatments are virtually out of reach in low- and middle-income countries due to significant price markups and barriers to generic manufacturing.The study conducted by Médecins Sans Frontières (MSF) was published this week in JAMA Open Network. Investigators estimated the cost of manufacturing insulins, GLP-1s and SGLT2 inhibitors, then calculated "sustainable" cost-based prices and compared these with current market prices for serval products. The market prices were derived from 13 countries, collected from public databases in January 2023.