Gemfibrozil

RAFT 试剂在聚合物化学中的应用，它们也用作各种杂环合成的前体， 包括青霉素类抗生素和吡唑并嘧啶，是有效的酪氨酸激酶抑制剂。因此，已经描述了多种合成二硫酯的方法，每种方法都有其自身的优缺点。它们最常用的合成方法是Grignard 试剂与二硫化碳反应生成的羰基二硫盐的烷基化（Scheme 1a ）。对空气敏感的Grignard 试剂的制备存在局限性试剂以及挥发性二硫化碳的高毒性是这种方法的主要问题。另一种广泛应用的二硫酯合成方法是使用硫酰化试剂，如P4S10 、劳森试剂和其他有机磷硫酯与羧酸（Scheme 1b)。然而，这种方法需要高温或长时间反应。此外，市售的劳厄森试剂在高温下不稳定，P4S10 需要在使用前纯化以确保可靠的结果。Scheme 1众所周知，1,3‑ 二硫烷衍生物在适当的碱，如n-BuLi 的作用下，容易在C(2) 位金属化位置，因此在有机合成中作为掩蔽酰负离子等价物发挥着不可或缺的作用。与1,3‑ 二硫烷不同，它们的五元类似物1,3‑ 二硫杂环在相同位置去质子化时容易发生环断裂，产生二硫羧酸根阴离子和乙烯气体（Scheme 2a)。此外，根据反应条件（溶剂的性质、碱和环上的取代基），1,3‑ 二硫杂环也可以在C(4) 位去质子化，生成硫醛和乙烯硫负离子（Scheme 2a)为了充分发挥碱诱导的1,3‑ 二硫杂环断裂的合成潜力，必须仔细调节反应条件。Scheme 2我们将这种断裂视为具有一锅合成二硫酯的潜力。在优化的条件下，我们发现使用 LiHMDS 在 CPME（环戊基甲基醚）中于 100°C 仅需 5 分钟（Scheme 2b ）即可选择性地在二硫烷环的 C(2) 位脱质子。相应的二硫羧酸酯随后被各种烷基卤化物和二芳基碘盐捕获，以提供一系列二硫酯。Cava 等人于 1979 年采用相同策略合成了甲基二硫酯，至今仍保持不变（Scheme 2c ）。他们报道了 5例甲基二硫酯的合成，平均产率为 52%。他们使用NaH 作为碱，在 DMF 和 HMPA 的混合物中于 130至 150 °C 下反应 2 小时可以提供2‑ 芳基‑1,3‑ 二硫烷的断裂。在第二步中，中间二硫羧酸盐在室温下通过甲基碘的加成进行甲基化。以开发二硫酯的通用合成方法为目标，我们通过筛选 1a 与五种不同碱（ KOtBu, NaH, NaHMDS,KHMDS, 和 LiHMDS ）在 CPME 中不同温度下与溴乙烷（Entry 1−8, Table 1 ）的一锅反应来启动我们的研究。Table 1其中，1.0 当量的 LiHMDS 在 100 °C 下 2 小时内实现了77% 的产率（Entry 5 ）。接下来，我们测试了 1a 与LiHMDS 在各种溶剂中的反应，发现 CPME 是最佳选择（Entry 9−12 ）。碱的当量（Entry13−15 ）似乎是反应成功的关键因素，而不是反应浓度（Entry 15−16 ）或HMPA 作为添加剂的存在（Entry 17 ）。基于这些发现，我们确定最佳反应条件是Entry 16 中描述的那些条件。在优化条件下，我们接下来使用各种取代的2‑ 芳基‑1,3‑ 二硫烷与溴乙烷反应，以探索这种一锅、一步法合成二硫酯衍生物的适用范围和局限性（Scheme 3 ）。Scheme 3除了2h 和2l 分别具有4‑( 三氟甲基) 苯基和呋喃基外，所有具有不同电子和空间效应的二硫酯衍生物（ 2a−g, 2i−k ）均以良好产率（ 60−89% ）获得。另一方面，2‑ 环己基‑1,3‑ 二硫烷（ 1m ）的反应没有产生相应的二硫酯2m。该反应以20% 的产率生成了酮烯二硫乙酰醛衍生物， α,α‑ 双（硫乙基） ‑ 亚甲基环己烷2m′，同时还有未反应的起始二硫烷（ 1m ）。没有α‑ 氢的二硫烷1n 的反应可以以13%的产率生成二烷基取代的二硫酯2n，但需要延长反应时间（ 18 小时）。当用较长的烷基溴代替溴乙烷时，1a 的反应也成功，分别以80% 和85% 的产率得到二硫酯3a 和4a。有趣的是，在优化条件下，1a 与苄基溴反应生成的相应二硫酯（ 5a−7a ）产率较低（ 31−35% ）。我们设想分两步进行反应可能会提高产率。因此，在第一步中，我们尝试在CPME 中于100°C 使用1.2 当量的LiHMDS 与1a 反应生成二硫羧酸根阴离子。3 分钟后，在100°C 下将苄基溴（如4‑ 氯苄基溴）添加到 resulting 深红色溶液中，将6a 的产率提高到68%。我们发现需要在第一步中使用0.5 当量的HMPA 并将反应时间延长至5 分钟，以在80% 的产率下获得6a。我们意识到在第二步中，加入1.1 当量的4‑ 氯苄基溴并在100°C 下搅拌混合物30 分钟就足以完成反应。Scheme 4我们随后研究了使用各种取代的苄基卤化物的一锅两步反应的适用范围。如图Scheme 4 所示，无论苯甲基上的取代基的电子性质和位置如何，都得到了二硫酯衍生物45a−19a，21a ，产率为65−84%。在优化的条件下，杂芳基苄基卤化物与1a反应良好，得到二硫酯20a，22a−25a，产率为66−82%。此外，我们还筛选了除苄基卤化物以外的底物，例如甲基‑2‑ 溴丙酸酯、烯丙基溴化物和溴乙腈以扩大该方法的应用范围。这些烷化试剂都给出了相应的二硫酯16a 、26a−27a，产率良好（ 66−79% ）。在最佳反应条件下，该方法还应用于药物吉非罗齐和奥沙普隆的衍生化，分别以72% 和52%的产率提供了相应的二硫酯28a−29a。接下来，我们通过在第二步中使用碘甲烷探索了2‑芳基‑1,3‑ 二硫烷（ 1a−g 、1i−l ）的适用范围。总体而言，带有给电子或吸电子取代基的芳基1,3‑ 二硫烷和2‑杂芳基‑1,3‑ 二硫烷在35 分钟的反应时间内以73−90% 的产率提供了甲基二硫酯30a−g 和30i−l。另一方面，碘甲烷与1a 的反应在上述一锅一步法中仅给出了33% 的产率。此外，该步骤还使用迈克尔受体（如丙烯腈和甲基丙烯酸酯）进行了测试，以进一步拓宽该方法的应用范围，但在优化条件下，这些反应的结果并不理想。Scheme 5为了展示该方法合成上的实用性，我们进行了 10.0 毫摩尔规模的反应，1a 没有使用手套箱，并在 THF 中使用市售的 LiHMDS 溶液（Scheme 5 ）。1a 与乙基溴化物在 CPME 和THF 的混合物中进行了单锅、一步反应，顺利得到二硫酯2a ，产率为 84% （ 1.65 克）。我们还以单锅、两步的方式进行了 1a 与苄基溴化物的反应。在这种情况下，反应得到二硫酯 5a ，产率为 68% （ 1.76 克），这低于在仅使用CPME 下 0.5 毫摩尔的 1a 所获得的 82% 产率，在优化的条件下。当使用碘甲烷进行相同步骤时，产物30a 以 83% 的产率（ 1.51 克）被分离出来。Scheme 6最后，鉴于在二硫酯阴离子与二芳基碘盐对硫中心亲核试剂的芳基化方面取得了成功的结果，我们尝试在无过渡金属的条件下芳基化二硫羧酸阴离子，以提供二芳基二硫酯（Scheme 6 ）。我们首先在CPME 中于100°C 下以LiHMDS 存在下对1a 和三苯基碘鎓进行了一锅、一步反应2 小时，生成了31a，产率仅为20%。然后我们决定分两步进行反应，正如对苄基卤化物所描述的那样。然而，我们发现第二步的反应时间必须延长至3 小时以获得最佳产率。由于抗衡阴离子会影响二芳基碘盐的活性，因此我们测试了1a 与具有三氟甲磺酸根、六氟磷酸根、氯和碘抗衡阴离子的三苯基碘盐的反应。其中，三苯基六氟磷酸盐表现最佳，生成了73% 产率的二硫酯31a。为了研究反应的适用范围，我们接下来将2‑ 芳基‑1,3‑ 二硫烷与具有不同电子和空间位阻性质的市售二芳基碘盐进行偶联。总体而言，无论芳基的电子性质如何，二芳基二硫酯(31a−36a, 31c−d, g, 和31i−k) 均以中等至良好的产率生成。二硫烷(1a 和1e−f) 与位阻较大的二( 均三甲苯基) 碘盐的反应也成功进行，分别生成了相应的产物37a(64% 产率) 和37e−f(76% 和83% 产率)。另一方面，当2‑( 邻甲苯基)‑1,3‑ 二硫烷与三苯基碘鎓反应时，分离得到了34% 产率的二硫酯31j。这表明二硫烷环上芳基的空间位阻对反应的成功影响更大。总之，我们深入研究了先前研究较少的碱介导的2‑芳基‑1,3‑ 二硫烷断裂，并将其确立为一种有效的方法在短时间内合成多种二硫酯，并通常具有良好的产率。该方法的一个关键优势在于起始化合物2‑ 芳基‑1,3‑二硫烷可以很容易地制备，甚至在室温下1 分钟内使用众所周知的程序。此外，所提出的方法操作简单，能够在克级规模上合成二硫酯。Org. Lett. 2025, 27, 16, 4135–4139（https://doi.org/10.1021/acs.orglett.5c00666）

Late-breaking results from the open-label compensated MASH cirrhosis (F4c) arm of the Phase 3 MAESTRO-NAFLD-1 trial presented at the EASL Congress 65% of patients with clinically significant portal hypertension (CSPH) at baseline moved into lower risk categories by year two Patients achieved a mean 6.7 kPa reduction in liver stiffness, which was statistically significant compared to baseline CONSHOHOCKEN, Pa., May 10, 2025 (GLOBE NEWSWIRE) -- Madrigal Pharmaceuticals, Inc. (NASDAQ: MDGL), a biopharmaceutical company focused on delivering novel therapeutics for metabolic dysfunction-associated steatohepatitis (MASH), today announced positive two-year results from the open-label compensated MASH cirrhosis (F4c) arm of the Phase 3 MAESTRO-NAFLD-1 trial of Rezdiffra. Patients (n=122) in the study achieved significant improvements from baseline in liver stiffness, liver fat, fibrosis biomarkers, liver volume and risk scores for clinically significant portal hypertension (CSPH). “Rezdiffra demonstrated broad, sustained efficacy across multiple noninvasive parameters at two years of treatment. A high, statistically significant percentage of patients with CSPH or probable CSPH at baseline shifted to lower risk categories,” said Naim Alkhouri, M.D., Chief Academic Officer at Summit Clinical Research and the Director of the Steatotic Liver Disease Program at the Clinical Research Institute of Ohio. “A larger placebo-controlled study will be needed to confirm Rezdiffra’s benefit in F4c, but the totality of data in this high-risk population of patients on the cusp of progressing to liver decompensation is highly encouraging as we await results from the ongoing Phase 3 MAESTRO-NASH OUTCOMES trial of Rezdiffra.” CSPH is a major consequence of cirrhosis and is responsible for its most severe complications, including ascites, variceal bleeding and hepatic encephalopathy. Patients with MASH who progress to cirrhosis face a 42 times higher risk of liver-related mortality. MAESTRO-NAFLD-1 included an open-label active treatment arm of patients with compensated MASH cirrhosis. After one year, patients were given the option to enroll in an open-label extension trial; 122 patients enrolled and 113 completed two years of treatment. At baseline, 35% of patients met Baveno criteria for CSPH, 14% for probable CSPH and 51% for no/low CSPH. The Baveno criteria use a combination of vibration-controlled transient elastography (VCTE) and platelet count to assess CSPH risk. Among patients with CSPH at baseline, 65% moved into lower risk categories by year two (42% to no/low CSPH and 23% to probable CSPH). Among patients with probable CSPH at baseline, 57% moved into the no/low CSPH category as compared to 14% who moved into the CSPH category by year two. Improvement in CSPH risk was statistically significant compared to baseline. Similar shifts to lower risk categories were observed in an analysis using a more stringent modified Baveno criteria that incorporates magnetic resonance elastography (MRE) and the Enhanced Liver Fibrosis (ELF) test as additional evidence for CSPH risk. As previously reported, patients achieved a mean 6.7 kPa reduction in liver stiffness at two years, which was statistically significant compared to baseline. In a responder analysis examining ≥25% improvement or worsening of liver stiffness, 51% of patients achieved improvement. An improvement of this magnitude has been associated with reduced progression to end-stage liver disease.1 Rezdiffra helped 35% of patients achieve liver stiffness measurements consistent with F3 fibrosis, suggesting reversal of cirrhosis. Safety data were consistent with previous studies and Rezdiffra was well-tolerated with a low rate of discontinuation due to adverse events. The most common adverse events were diarrhea, COVID-19 and nausea. There were two deaths unrelated to Rezdiffra. “Lower thyroid-hormone receptor-beta (THR-β) activity in the liver is predictive of hepatic decompensation2 in patients with MASH, so there is a strong mechanistic rationale supporting the potential of Rezdiffra, a THR-β agonist, to improve outcomes in patients with compensated MASH cirrhosis,” said David Soergel, M.D., Chief Medical Officer of Madrigal. “These two-year open-label data from MAESTRO-NAFLD-1 add important clinical evidence that supports our confidence in the ongoing, fully enrolled Phase 3 outcomes trial of Rezdiffra in compensated MASH cirrhosis.” Investor Webcast to Review New F4c Data At 8 a.m. EDT May 13, 2025, Madrigal will host a webcast to review the detailed two-year data from the compensated MASH cirrhosis (F4c) arm of the Phase 3 MAESTRO-NAFLD-1 trial. To access the webcast, please visit the investor relations section of the Madrigal website or click here to register. About MASH Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is a serious liver disease that can progress to cirrhosis, liver failure, liver cancer, need for liver transplantation, and premature mortality. MASH is expected to become the leading cause of liver transplantation in the U.S. and is already the leading cause of liver transplantation among women. Once patients progress to MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), the risk of adverse liver outcomes increases dramatically: these patients have a 10-17 times higher risk of liver-related mortality as compared to patients without fibrosis. Those who progress to cirrhosis face a 42 times higher risk of liver-related mortality, underscoring the need to treat MASH before complications of cirrhosis develop. MASH is also an independent driver of cardiovascular disease, the leading cause of mortality for patients. An estimated 1.5 million patients have been diagnosed with MASH in the U.S., and Madrigal is focused on reaching approximately 315,000 patients with moderate to advanced fibrosis who are under the care of liver specialists. As MASH disease awareness improves and disease prevalence increases, the number of diagnosed patients with MASH with moderate to advanced fibrosis is expected to grow. About Rezdiffra Rezdiffra is a once-daily, oral, liver-directed THR-β agonist designed to target key underlying causes of MASH. It is the first approved medication for the treatment of MASH in the U.S. In the pivotal Phase 3 MAESTRO-NASH biopsy trial, Rezdiffra achieved both fibrosis improvement and MASH resolution primary endpoints, and 91% of patients treated with Rezdiffra 100 mg experienced improvement or stabilization of liver stiffness. In the U.S., Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). Continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials. Rezdiffra is not approved in Europe for the treatment of patients with MASH with moderate to advanced liver fibrosis and not approved in any geography for the treatment of patients with cirrhosis. The ongoing, fully enrolled MAESTRO-NASH OUTCOMES trial is evaluating progression to liver decompensation events in patients with compensated NASH cirrhosis treated with Rezdiffra versus placebo. A positive outcome is expected to support the full approval of Rezdiffra for noncirrhotic MASH and expand the eligible patient population for Rezdiffra with an additional indication in patients with compensated MASH cirrhosis. What is Rezdiffra? Rezdiffra is a prescribed medicine used along with diet and exercise to treat adults with nonalcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), but not with cirrhosis of the liver. It is not known if Rezdiffra is safe and effective in children (under 18 years old). This indication is approved based on improvement of NASH and liver scarring (fibrosis). There are ongoing studies to confirm the clinical benefit of Rezdiffra. Before you take Rezdiffra, tell your healthcare provider about all of your medical conditions, including if you: have any liver problems other than NASH. have gallbladder problems or have been told you have gallbladder problems, including gallstones. are pregnant or plan to become pregnant. It is not known if Rezdiffra will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if Rezdiffra passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Rezdiffra. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Rezdiffra and other medicines may affect each other, causing side effects. Rezdiffra may affect the way other medicines work, and other medicines may affect how Rezdiffra works. Especially tell your healthcare provider if you take medicines that contain gemfibrozil to help lower your triglycerides, or cyclosporine to suppress your immune system, because Rezdiffra is not recommended in patients taking these medicines. Tell your healthcare provider if you are taking medicines such as clopidogrel to thin your blood or statin medicines to help lower your cholesterol. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. What are the possible side effects of Rezdiffra? Rezdiffra may cause serious side effects, including: liver injury (hepatotoxicity). Stop taking Rezdiffra and call your healthcare provider right away if you develop the following signs or symptoms of hepatotoxicity: tiredness, nausea, vomiting, fever, rash, your skin or the white part of your eyes turns yellow (jaundice), pain or tenderness in the upper middle or upper right area of your stomach (abdomen). gallbladder problems. Gallbladder problems such as gallstones, inflammation of the gallbladder, or inflammation of the pancreas from gallstones can occur with NASH and may occur if you take Rezdiffra. Call your healthcare provider right away if you develop any signs or symptoms of these conditions including nausea, vomiting, fever, or pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen to your back and the pain may happen with or without vomiting. The most common side effects of Rezdiffra include: diarrhea, nausea, itching, stomach (abdominal) pain, vomiting, dizziness, constipation. These are not all the possible side effects of Rezdiffra. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Madrigal at 1-800-905-0324. Please see the full Prescribing Information, including Patient Information, for Rezdiffra. About Madrigal Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) is a biopharmaceutical company focused on delivering novel therapeutics for metabolic dysfunction-associated steatohepatitis (MASH), a liver disease with high unmet medical need. Madrigal’s medication, Rezdiffra (resmetirom), is a once-daily, oral, liver-directed THR-β agonist designed to target key underlying causes of MASH. Rezdiffra is the first and only medication approved by the FDA for the treatment of MASH with moderate to advanced fibrosis (consistent with stages F2 to F3). An ongoing Phase 3 outcomes trial is evaluating Rezdiffra for the treatment of compensated MASH cirrhosis (consistent with stage F4c). For more information, visit www.madrigalpharma.com. Forward-Looking Statements This press release includes “forward-looking statements” made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended, including statements related to the potential benefit of Rezdiffra in patients with compensated MASH cirrhosis. Forward-looking statements are subject to a number of risks and uncertainties including, but not limited to: the assumptions underlying the forward-looking statements; risks of obtaining and maintaining regulatory approvals, including, but not limited to, potential regulatory delays or rejections; the challenges with the commercial launch of a new product, particularly for a company that did not have commercial experience prior to 2024; our history of operating losses and the possibility that we may never achieve or maintain profitability; risks associated with meeting the objectives of Madrigal’s clinical trials, including, but not limited to Madrigal’s ability to achieve enrollment objectives concerning patient numbers (including an adequate safety database), outcomes objectives and/or timing objectives for Madrigal’s trials; any delays or failures in enrollment, and the occurrence of adverse safety events; risks related to the effects of Rezdiffra’s (resmetirom’s) mechanism of action; market demand for and acceptance of Rezdiffra; the potential inability to raise sufficient capital to fund ongoing operations as currently planned or to obtain financing on acceptable terms; our ability to service indebtedness and otherwise comply with debt covenants; outcomes or trends from competitive trials; future topline data timing or results; our ability to prevent and/or mitigate cyber-attacks; the uncertainties inherent in clinical testing; uncertainties concerning analyses or assessments outside of a controlled clinical trial; and changes in laws and regulations applicable to our business and our ability to comply with such laws and regulations. Undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made. Madrigal undertakes no obligation to update any forward-looking statements to reflect new information, events, or circumstances after the date they are made, or to reflect the occurrence of unanticipated events. Please refer to Madrigal’s submissions filed with the U.S. Securities and Exchange Commission(“SEC”), for more detailed information regarding these risks and uncertainties and other factors that may cause actual results to differ materially from those expressed or implied. Madrigal specifically discusses these risks and uncertainties in greater detail in the sections appearing in Part I, Item 1A of its Annual Report on Form 10-K for the year ended December 31, 2024, filed with the SEC on February 26, 2025, and as updated from time to time by Madrigal’s other filings with the SEC. 1. Lin H, Lee HW, Yip TC, et al. Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease. JAMA. 2024;331(15):1287–1297. 2. Kendall TJ, Jimenez-Ramos M, Turner F, et al. An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease. Nat Med. 2023 Nov;29(11):2939-2953. Investor Contact Tina Ventura, IR@madrigalpharma.com Media Contact Christopher Frates, media@madrigalpharma.com Source: Madrigal Pharmaceuticals, Inc.