Mavorixafor

BOSTON and DUBAI, United Arab Emirates, Feb. 19, 2025 (GLOBE NEWSWIRE) -- X4 Pharmaceuticals (Nasdaq: XFOR), a company driven to improve the lives of people with rare diseases of the immune system, and taiba rare, a taiba Healthcare company with specialty & orphan drug marketing, sales, and distribution expertise in the MENA (Middle East and North Africa) region, today announced that they have entered into an exclusive agreement for the distribution and commercialization of XOLREMDI® (mavorixafor), an oral, once-daily treatment for WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis), in select Middle East countries (Saudi Arabia, United Arab Emirates, Qatar, Oman, Kuwait, Bahrain, and Egypt), following any approvals in the region. XOLREMDI (mavorixafor) was approved by the U.S. Food and Drug Administration (FDA) in April 2024 for the treatment of patients 12 years of age and older with WHIM syndrome, a rare primary immunodeficiency, to increase the number of circulating mature neutrophils and lymphocytes. The Marketing Authorization Application (MAA) for mavorixafor for the treatment of WHIM syndrome is currently under review by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP). “We are very pleased to collaborate with taiba rare, an ideal partner for X4 due to their dedication to and experience providing access to innovative rare disease treatments throughout the region,” said Paula Ragan, Ph.D., President and Chief Executive Officer of X4 Pharmaceuticals. “We look forward to working together to further expand the global reach of XOLREMDI for people with WHIM syndrome.” Saif Al Hasani, Chief Executive Officer of taiba Healthcare, commented on the announcement: “XOLREMDI is the first and only treatment approved for patients with WHIM syndrome. We are proud to partner with X4 to bring XOLREMDI to those with this rare primary immunodeficiency in the Middle East region. Having been granted Orphan Drug Designation in both the U.S. and the European Union, XOLREMDI fits well into our portfolio of innovative therapies for those with the highest unmet needs.” taiba will lead the distribution, promotion, marketing, and sales of XOLREMDI within the territory, working jointly with X4 on key strategic decisions. Local regulatory filings for XOLREMDI approval will be based on X4’s registration dossier submitted to the U.S. FDA. Pending any regulatory approvals in the region, taiba is expected to be able to provide XOLREMDI to WHIM patients through a named-patient (compassionate use) program that allows physicians to prescribe medicines approved in other countries to local patients with no other treatment options. IMPORTANT SAFETY INFORMATION CONTRAINDICATION XOLREMDI is contraindicated with drugs highly dependent on CYP2D6 for clearance. WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: Based on its mechanism of action, XOLREMDI is expected to cause fetal harm when administered to a pregnant woman. Verify pregnancy status of female patients of reproductive potential prior to starting XOLREMDI. Advise females of reproductive potential to use effective contraception during treatment with XOLREMDI and for three weeks after the final dose. QTc Interval Prolongation: XOLREMDI causes concentration-dependent QTc prolongation. QTc prolongation may occur when XOLREMDI is taken with concomitant medications that increase XOLREMDI exposure and/or drug products with a known potential to prolong QTc. Correct any modifiable risk factors for QTc prolongation, assess QTc at baseline, and monitor QTc during treatment as clinically indicated in patients with risk factors for QTc prolongation or receiving concomitant medications that increase XOLREMDI exposure and/or drugs with a known potential to prolong the QTc interval. Dose reduction or discontinuation of XOLREMDI may be required. ADVERSE REACTIONS The most common adverse reactions (in ≥10% patients and more frequently reported than placebo) were thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness. DRUG-DRUG INTERACTIONS Avoid co-administration of XOLREMDI and strong CYP3A4 inducers. Reduce XOLREMDI daily dosage when administered with strong CYP3A4 inhibitors. Monitor more frequently for adverse reactions associated with an increase in exposure of XOLREMDI when used concomitantly with moderate CYP3A4 inhibitors or P-gp inhibitors and reduce XOLREMDI daily dosage if necessary. USE IN SPECIFIC POPULATIONS Advise females that breastfeeding is not recommended during treatment with XOLREMDI and for three weeks after the final dose. The safety and effectiveness of XOLREMDI have not been established in pediatric patients younger than 12 years of age. XOLREMDI is not recommended in patients with severe renal impairment, end-stage renal disease, or moderate to severe hepatic impairment. To report suspected adverse reactions, contact X4 Pharmaceuticals at 1-866-MED-X4MI (1-866-633-9464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see the full Prescribing Information for XOLREMDI. About WHIM Syndrome WHIM syndrome is a rare, combined primary immunodeficiency and chronic neutropenic disorder caused by CXCR4 receptor dysfunction that results in impaired mobilization of white blood cells from the bone marrow into peripheral circulation. WHIM syndrome is named for its four classic manifestations: warts, hypogammaglobulinemia, infections, and myelokathexis, although only a minority of patients experience all four manifestations in the acronym. People with WHIM syndrome characteristically have low blood levels of neutrophils (neutropenia) and lymphocytes (lymphopenia), and as a result, experience serious and/or frequent infections. About XOLREMDI® (mavorixafor) XOLREMDI (mavorixafor) is a selective CXCR4 receptor antagonist approved in the U.S. as a once-daily oral treatment for use in patients 12 years of age and older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. XOLREMDI is the only treatment specifically approved for patients with WHIM syndrome in the U.S. About X4 Pharmaceuticals X4 is delivering progress for patients by developing and commercializing innovative therapies for those with rare diseases of the immune system and significant unmet needs. Leveraging expertise in CXCR4 and immune system biology, X4 has successfully developed mavorixafor, an orally available CXCR4 antagonist that is currently being marketed in the U.S. as XOLREMDI® in its first indication. The company is also evaluating additional uses of mavorixafor and is conducting a global, pivotal Phase 3 clinical trial (4WARD) in people with certain chronic neutropenic disorders. X4 is headquartered in Boston, Massachusetts. For more information, please visit www.x4pharma.com. About taiba Healthcare Established in 1980, taiba Healthcare is a leading specialty marketing, sales and distribution company in the MENA region providing innovative treatments to patients with orphan and rare diseases either through early access programs or through commercialization. taiba’s vision is to cover the unmet medical need in its region providing breakthrough products and high level of service to healthcare organizations and commitment to patient treatment. Over the last 40 years, taiba has earned a reputation as a leading regional company in rare diseases by actively seeking opportunities to collaborate with healthcare professionals, organizations, and institutions, for the benefit of patients. X4 Forward Looking Statements This press release contains forward-looking statements within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995, as amended. These statements may be identified by the words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target,” or other similar terms or expressions that concern X4’s expectations, strategy, plans, or intentions. Forward-looking statements include, without limitation, implied or express statements regarding compiling and submitting regulatory submissions in the select Middle East countries and the potential for approval in the select Middle East countries; the initiation, timing, progress, and results of X4’s current and future preclinical studies and clinical trials; the timing and anticipated interactions with regulatory authorities and any related approvals for mavorixafor in Saudi Arabia, United Arab Emirates, Qatar, Oman, Kuwait, Bahrain, and Egypt; the potential market opportunity for mavorixafor; the anticipated strategic benefits of X4’s exclusive agreement for the distribution and commercialization with taiba and of any current or future collaborations; and the mission and goals for X4’s business. Any forward-looking statements in this press release are based on management’s current expectations and beliefs. These forward-looking statements are neither promises nor guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond X4’s control, which could cause actual results to differ materially from those contemplated in these forward-looking statements, including the risks that: there are uncertainties inherent in the regulatory approval process in the select Middle East Countries including the timing, progress, and outcome of their review; potential delays or difficulties in commercializing mavorixafor in the Middle East if regulatory approval is granted; challenges in coordinating with external partners including taiba; X4 may have difficulty establishing and maintaining an effective sales and marketing organization or suitable third-party alternatives for any approved products; X4 may not be able to obtain or maintain orphan drug designation or exclusivity for X4’s drug candidates, which could limit the potential profitability of X4’s product candidates; X4 may not be able to obtain regulatory approval for, or successfully commercialize, mavorixafor or any other product candidate for any chronic neutropenic disorder or any other potential indication; the expected availability, content, and timing of clinical data from X4’s ongoing clinical trials of mavorixafor may be delayed or unavailable, including X4’s ongoing Phase 3 clinical trial; the design and rate of enrollment for clinical trials, including the current design of a Phase 3 clinical trial evaluating mavorixafor in certain chronic neutropenic disorders may not enable successful completion of the trial(s); X4’s business could be substantially harmed due to the lengthy, time-consuming and inherently unpredictable regulatory review and approval processes of the FDA and comparable foreign regulatory authorities , and X4 may ultimately be unable to obtain regulatory approval for X4’s product candidates, including additional indications for mavorixafor; the need to align with X4’s collaborators may hamper or delay X4’s development and commercialization efforts or increase X4’s costs; X4’s business may be adversely affected and their costs may increase if any of X4’s key collaborators fails to perform its obligations or terminates the collaboration; the internal and external costs required for X4’s ongoing and planned activities, and the resulting impact on expense and use of cash, may be higher than expected, which may cause the company to use cash more quickly than expected or to change or curtail some of X4’s plans or both; and other risks and uncertainties, including those described in the section entitled “Risk Factors” in X4’s Quarterly Report on X4’s Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 13, 2024, and in other filings X4 makes with the SEC from time to time. X4 undertakes no obligation to update the information contained in this press release to reflect new events or circumstances, except as required by law. X4 Investor Contact: Daniel Ferry LifeSci Advisors daniel@lifesciadvisors.com (617) 430-7576 X4 Media Contact: Rhiannon Jeselonis Ten Bridge Communications rhiannon@tenbridgecommunications.com taiba Contact Abdulaziz Alhasani media@taibahealthcare.com Source: X4 Pharmaceuticals

DOI: 10.1016/j.ejmech.2025.117241  2024年，FDA批准了50种新药，包括32种新化学实体（NCE）和18种生物实体（NBE）。在获批新药中，小分子化学药仍是创新主力，以64%的比例遥遥领先，涵盖了LACTB、PBP、THR-β、Raf、PDE3/4、HIF等靶点。 单克隆抗体紧随其后的是13种药物（26%）、2种基于蛋白质的药物（4%）、2种小核酸药物（4%）和1种甲状旁腺激素类似物（2%）。 近期（Jan. 4），吉林大学中日联合医院在Eur. J. Med. Chem.上刊载了对2024年FDA批准的32种小分子实体的合成和应用汇总。 01 2024年FDA批准小分子总览 1.1、2024获批新药 2024年，美国FDA批准了50种新药，包括32种新化学实体（NCE）和18种生物实体（NBE）,其药物名称、活性成分、获批日期、适应症等信息如下表所示。 2024年FDA批准新药数量相比2023年没有显著差异，“同类首创新药”（First-in-Class，FIC）的数量也基本相同：2023年获批20种FICs，占当年获批药物总数36%；2024年获批22种FICs，占当年获批药物总数44%。 在这些FICs中，小分子药物几乎占了一半（10种），抗体药物则是占据了另一个主要部分（5种单克隆抗体、3种双特异性抗体）。 就疾病治疗领域而言，肿瘤（28%）仍然是2024年FDA批准新药数量最多的领域；其次是罕见病（20%），然后是心血管和代谢疾病、传染病、自身免疫性疾病、皮肤病、精神和神经疾病、以及其它疾病领域。 1.2、2024获批小分子新化学实体（NCE） 如下图，是2024年FDA批准小分子实体的具体结构。本文重点介绍了这些新化学实体的合成和临床应用，旨在深入了解其作用机制、治疗潜力、合成路径。 02 抗感染药物 2.1、Exblifep (Cefepime、Enmetazobactam) Exblifep是一种组合用药，由头孢吡肟和恩美唑巴坦联合使用，用于治疗复杂的尿路感染。 其中，头孢吡肟是BMS开发的第四代头孢菌素抗生素，于1996年获FDA批准，用于各种细菌的感染。该药物通过抑制细菌细胞壁合成，靶向参与细胞壁形成最后阶段的青霉素结合蛋白（PBPs）起作用；其对革兰氏阳性和阴性细菌都有广谱活性。 其合成路线见下图方案1。 恩美唑巴坦是由Rib-X制药公司开发的β-内酰胺酶抑制剂，用于增强β-内酰胺类抗生素的活性，特别是针对多重耐药的革兰氏阴性菌。 该药物通过抑制A类、C类、和一些D类β-内酰胺酶（分解β-内酰胺类抗生素的酶）起作用，从而恢复头孢吡肟等抗生素对耐药菌株的疗效，有效保护头孢吡肟不被耐药菌株水解。 该药物的合成路线见下图方案2。 2.2、Zevtera (Ceftobiprole Medocaril Sodium) 头孢菌素钠是Basilea制药公司开发，获批用于治疗某些血液感染、细菌性皮肤和相关组织感染、以及社区获得性细菌性肺炎。 该药物通过结合PBPs，抑制细菌细胞壁合成，导致细胞裂解。它对革兰氏阳性和阴性病原体都有广谱活性。 其合成路线见下图方案3。 2.3、Orlynvah (Sulopenem etzadroxil and probenecid) Orlynvah也是一种联合用药，由Sulopenem entzadroxil和Probenecid联用，用于治疗非并发症尿路感染。 其中，Sulopenem entzadroxil是由Melinta Therapeutics开发，通过结合PBPs抑制细菌细胞壁合成，导致细胞死亡；该药物设计用于抵抗β-内酰胺酶的水解，使其对耐药病原体的活性增强。 其合成路线见下图方案4。 Probenecid是由GSK开发，于1951年获批用于治疗痛风和高尿酸血症。该药物的工作原理是抑制肾小管对富尿酸的重吸收，从而增加其在尿液中的分泌，减少关节内尿酸晶体的积聚，减轻痛风症状。 其合成路线见下图方案5。 03 肿瘤药物 3.1、Ojemda (tovorafenib) Tovorafenib是Mirati Therapeutics公司开发的一种选择性RAF激酶抑制剂，获批用于治疗复发或难治性儿童低级别胶质瘤。 该药物通过选择性抑制BRAF V600突变激酶起作用；BRAF V600突变激酶是许多癌症（包括黑色素瘤、非小细胞肺癌（NSCLC）和结直肠癌）发生的关键驱动因素。通过抑制BRAF，该药物阻止MAPK通路的下游信号传导，减少肿瘤细胞的增殖。 其合成路线见下图方案6。 3.2、Voranigo (vorasidenib) Vorasidenib是由Agios制药公司开发的IDH1/IDH2抑制剂，获批用于治疗2级星形细胞瘤或少突胶质细胞瘤。 该药物通过抑制突变体IDH1和IDH2酶起作用，这两种酶参与2-羟基戊二酸（2-HG）的产生，2-羟基戊二酸是一种促进肿瘤发生的非共代谢物。通过抑制突变的IDH酶，Vorasidenib降低2-HG水平，导致肿瘤生长抑制。 其合成路线见下图方案7。 3.3、Lazcluze (lazertinib) Lazertinib是由汉斯生物公司开发的第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），获批用于治疗NSCLC。 Lazertinib通过选择性抑制EGFR突变（包括T790 M和其它敏感突变）起作用，该突变与各种癌症的不受控制的细胞生长有关。通过靶向EGFR， Lazertinib抑制驱动肿瘤增殖和存活的下游信号通路。与一线EGFR抑制剂相比，Lazertinib显示出PFS和总生存期（OS）的改善。 其合成路线见下图方案8。 3.4、Itovebi (inavolisib) Inavolisib由Arcus Biosciences公司开发，是一种针对磷酸肌肽3激酶(PI3K) δ和γ亚型的等口服选择性抑制剂，获批用于治疗局部晚期或转移性乳腺癌。 通过抑制PI3Kδ和PI3Kγ，Inavolisib通过PI3k/AKT/mTOR信号通路抑制肿瘤生长和免疫调节。在临床前研究中，它显示出显著的抗肿瘤活性，特别是与免疫检查点抑制剂联合使用，表明增强了免疫监视和肿瘤控制。 其合成方案见下图方案9。 3.5、Revuforj (revumenib) Revumenib是由Kura Oncology开发的小分子抑制剂，获批用于治疗复发获难治性急性白血病。 该药物靶向和抑制menin，一种涉及基因表达失调的关键蛋白，特别是MLL-r突变。通过抑制menin，该药物破坏HOXA基因的转录激活，HOXA基因负责白血病的发生。 其合成方法见下图方案10。 3.6、Ensacove (ensartinib) 恩沙替尼是一种选择性小分子酪氨酸激酶抑制剂，由安斯泰来制药公司开发，用于治疗非小细胞肺癌。该药物获批用于对克唑替尼不耐受的NSCLC进展患者。 恩沙替尼靶向ALKand ROS1酪氨酸激酶，抑制它们的ATP结合位点，阻止肿瘤细胞生长。在临床前研究中，它显示出显著的抗肿瘤活性，降低了ALK驱动的非小细胞肺癌模型的肿瘤。 其合成路线见下图方案11。 04 冠心病药物 4.1、Tryvio (aprocitentan) Aprocitentan是一种内皮素受体拮抗剂，由Idorsia制药公司开发，获批用于治疗高血压。 该药物靶向内皮素A（ETA）和内皮素B（ETB）受体，这两个受体参与血管收缩和血压调节。其作用机制包括阻断内皮素受体，导致血管舒张和改善血压调节。临床前药效学表明，该药物能有效降低顽固性高血压动物模型的血压。 其合成路线见下图方案12。 4.2、Voydeya (danicopan) 达尼可潘（Danicopan）是一种补体C5a受体抑制剂，由Pharming Group开发，获批用于治疗血管外溶血合并突发性夜间血红蛋白尿。 达尼可潘通过抑制补体C5aR起作用，C5aR在PNH的病理生理中起着重要作用，介导炎症和红细胞破坏。通过阻断该受体，达尼可潘有助于减少PNH患者的溶血和改善贫血。 其合成路线见下图方案13。 4.3、Attruby (acoramidis) Acoramidis是由辉瑞开发的小分子稳定剂，用于治疗野生型或变异型转甲状腺素介导的淀粉样变性心肌病。 Acoramidis的工作原理是结合并稳定TTR蛋白，防止其错误折叠和聚集，这是导致淀粉样蛋白在心脏沉积的原因。这种稳定作用可减少ATTR-CM患者心功能障碍的进展。 其合成路线见下图方案14。 4.4、Rapiblyk (landiolol) Landiolol是一种β-1选择性肾上腺素能拮抗剂，由Kowa制药公司开发，用于治疗室上性心动过速。 该药物通过选择性阻断心脏中的β-1肾上腺素能受体，降低心率和心肌收缩力，从而帮助控制快速的心律。 其合成路线见下图方案15。 4.5、Vafseo (vadadustat) Vadadustat是由Akebia Therapeutics公司开发的口服缺氧诱导因子脯氨酸羟化酶抑制剂，用于治疗慢性肾病所致贫血。 Vadadustat通过抑制脯氨酰羟化酶起作用，从而导致缺氧诱导因子（HIFs）的稳定，从而增加红细胞生成和增强血红蛋白的产生。临床前药效学表明，vadadustat通过模拟缺氧的作用来增加红细胞的产生。 其合成路线见下图方案16。 05 中枢神经系统药物 5.1、Miplyffa (arimoclomol) 阿利莫洛尔（Arimoclomol）是由Orphazyme开发的热休克蛋白（HSPs）的小分子共诱变剂，用于治疗C型尼曼-匹克病。 阿利莫洛姆通过调节热休克蛋白起作用，热休克蛋白在细胞应激反应、蛋白质折叠和神经保护中发挥重要作用。这种机制有助于保护神经元免受错误折叠的蛋白质和与其他神经退行性疾病相关的细胞损伤。 该药物合成路线见方案17。 5.2、Aqneursa (levacetylleucine) Levacetylleucine（左旋乙酰亮氨酸）是一种氨基酸衍生物，由Eisai有限公司开发，用于治疗尼曼-匹克病C型。 该药物是乙酰胆碱的前体，参与认知功能和记忆的神经递质。通过增加大脑中的乙酰胆碱水平，左乙基亮氨酸有助于改善突触传递和认知能力。 其合成路线见下图方案18。 5.3、Cobenfy (xanomeline and trospium chloride) Cobenfy是一种联合用药，由xanomeline和trospium chloride联合使用，用于治疗精神分裂症。 Xanomeline是一种毒蕈碱乙酰胆碱受体激动剂，通过选择性刺激大脑中的毒蕈碱M1和M4受体起作用，这些受体与认知功能、记忆和精神疾病有关。通过靶向这些受体，xanomeline减少了多巴胺的过度活动，而多巴胺与精神分裂症和ADP的精神病症状有关。 Xanomeline合成路线见下图方案19： Trospium Chloride是由Generics Pharmaceutics开发的抗蛇毒碱制剂，用于治疗膀光过度活动（OAB）和尿失禁。 该药物通过阻断膀胱内的毒蕈碱受体（M3受体），抑制平滑肌收缩，减少尿急和尿频而起作用。 该药物的合成路线见下方路线20： 06 肌肉骨骼药物 6.1、Duvyzat (givinostat hydrochloride monohydrate) Givinostat由Italfarmaco开发，是一种HDAC抑制剂，用于治疗6岁及以上个体的杜氏肌营养不良症。 Givinostat通过抑制HDAC起作用，HDAC在调节基因表达、改善肌肉功能和促进肌肉修复方面发挥作用。在临床前药效学研究中，该药物在DMD动物模型中显示出肌肉力量的改善和肌肉退化的减少。 其合成路线见下图方案21: 07 放射性活性药物 7.1、Flyrcado (flurpiridaz F-18) 氟吡唑F-18是一种PET（正电子发射断层扫描）影像剂，由Lantheus Medical Imaging开发，用于冠状动脉（CAD）的PET成像诊断。 该药物是一种结合心脏内心肌灌注区，特异性靶向参与血管内张力调节的S1P（鞘氨醇-1-磷酸）受体的放射性标记化合物。通过发射正电子，它可以在PET扫描中显示心脏组织和血液流动。 其合成路线见下图方案22： 7.2、Iomervu (iomeprol) Iomeprol是Bracco Imaging开发的一种非离子碘化造影剂，可作为放射造影剂用于诊断成像程序，包括计算机断层扫描（CT）和血管造影。 Iomeprol的工作原理是通过碘的高原子序数在放射成像中提供对比度增强，从而在CT扫描中增加血管和组织的可见性。 其合成路线见下图方案23： 08 胃肠道药物 8.1、Iqirvo (elafibranor) Elafibranor 是一种Farnesoid X受体（FXR）激动剂，由Genfit研发，用于联合熊去氧胆酸治疗原发性胆管炎。 Elafibranor通过激活FXR起作用，FXR是一种核受体，在胆红酸稳态、脂质代谢和炎症中起核心作用。通过调节FXR， Elafibranor有助于减少肝脏脂肪积累、炎症和纤维化，这是NASH进展的关键因素。 其合成路线见下图方案24： 8.2、Livdelzi (seladelpar) Seladelpar是Genfit开发的一种过氧化物酶体增殖体激活受体δ (PPARδ)激动剂，用于治疗原发性胆管炎（PBC）。 Seladelpar通过激活PPARδ起作用，PPARδ是参与脂质代谢、炎症和纤维化过程的核受体。通过调节PPARδ，Seladelpar可减轻PBC患者的炎症和纤维化，改善肝功能并减缓疾病进展。 其合成路线见下图方案25： 09 自身免疫药物 9.1、Xolremdi (mavorixafor) Mavorixafor是X4制药公司开发的选择性CXCR4拮抗剂，用于治疗WHIM综合征（疣、低γ -球蛋白血症、感染和骨髓增生）和罕见的原发性免疫缺陷疾病。 Mavorixfor靶向CXCR4受体，阻断其激活，防止中性粒细胞留在骨髓中，从而增强其进入血液的动员。这可以改善免疫反应，降低感染易感性。 其合成方案见下图方案26： 9.2、Leqselvi (deuruxolitinib) Deuruxolitinib是由Incyte公司开发的Janus激酶（JAK）抑制剂，用于治疗重度斑秃。 Deuruxolitinib通过选择性抑制JAK1和Jak2起作用，JAK1和Jak2是JAK1-STAT信号通路中的关键酶，在骨髓纤维化和其他癌症中被失调。通过抑制这些酶，deuruxolitinib减少促炎细胞因子的产生和骨髓纤维化。 其合成路线见下图方案27： 10 内分泌药物 10.1、Sofdra (Sofpironium Bromide) Sofpironium Bromide由Sol-Gel Technologies开发的局部抗胆碱能药，用于治疗原发性腋下多汗症。 该药物的工作原理是选择性地抑制汗腺中的毒蕈碱受体（M3受体），减少汗液的产生。这种机制有助于缓解腋窝等部位的过度出汗。在临床前药效学研究中，该药物在动物模型中显示出有效和持久的抑制汗液分泌。 其合成路线见下图方案28： 10.2、Crenessity (crinecerfont) Creinecerfont是Concept Therapeutics公司开发的选择性促肾上腺皮质激素释放激素（CRH）受体1拮抗剂，用于治疗经典先天性肾上腺皮质增生症（CAH）。 Criinecerfont靶向并阻断CRH受体1(CRHR1)，从而减少皮质醇的产生和随后过量的雄激素分泌。在临床前研究中，在CAH动物模型中，Criinecerfont成功降低了升高的ACTH水平和正常化的激素产生。 其合成路线见下图方案29： 11 呼吸系统药物 11.1、Ohtuvayre (ensifentrine) Ensifentrine是中性粒细胞弹性酶和基质金属蛋白酶（MMPs）的抑制剂，由Verona Pharma开发，用于治疗慢性阻塞性肺疾病（COPD）。 Ensifentrine通过抑制中性粒细胞弹性酶（一种导致慢性阻塞性肺疾病组织损伤的酶）和基质金属蛋白酶（参与组织重塑和炎症）起作用。这种双重作用可以减少气道炎症，保护肺部免受进一步损害。 其合成方法见下图方案30： 12 护肝药物 12.1、Rezdiffra (resmetirom) 瑞司替罗（Resmetirom）是由Madrigal制药公司开发的THR-β (THR-β)激动剂，经FDA批准用于治疗中度至晚期肝瘢痕形成的非肝硬化非酒精性脂肪性肝炎。 Resmetirom通过选择性结合THR-β起作用，THR-β主要在肝脏中表达，改善脂质代谢，减少肝脏脂肪积累。临床前药效学研究表明雷司美替梅可减少肝脏脂肪变性和炎症。 其合成方法见下图方案31： 13 遗传病药物 13.1、Alyftrek (vanzacaftor, tezacaftor, and deutivacaftor) Alyftrek是一种混合用药，由vanzacactor， tezacactor和deutivactor组合联用。 其中Tezacaftor由Vertex制药公司开发，是FDA于2024年12月20日批准的与vanzacaftor和deutivacaftor联合治疗囊性纤维化（CF）的药物。 这种三联疗法针对并纠正各种CFTR突变患者的CFTR蛋白缺陷。Tezacaftor和vanzacaftor作为CFTR校正剂，改善蛋白质运输和功能，而deutivacaftor增强CFTR氯通道活性。这种结合有助于恢复正常的氯离子传输。 Tezacaftor的合成见下图方案32：