Buloxibutid

近日，由明尼苏达大学Courtney C. Aldrich研究团队在顶级药物化学期刊《Journal of Medicinal Chemistry》上发表了一项重要研究成果。该研究系统性披露了此前未公开的先导化合物优化全过程，通过理性的药物设计策略，成功开发出一系列靶向结核分枝杆菌生物素合成关键酶BioA的新型哌嗪类抑制剂。其中，明星化合物C48展现出皮摩尔级别的超强靶点抑制活性、对一系列敏感及耐药结核菌株的卓越抗菌效果，以及优异的口服药代动力学特性，已在模拟人体生物素生理水平的低生物素小鼠模型中证实了其体内疗效，标志着针对结核病这一古老传染病的新一代疗法开发取得了关键进展。 一、 研究背景：抗击结核病的持久战与新靶点机遇 结核病，由结核分枝杆菌（Mycobacterium tuberculosis, Mtb）感染引起的呼吸道传染病，至今仍是全球最致命的传染病之一。本研究将目光投向了结核菌的生物素合成通路。生物素是结核菌生存必需的辅因子，参与脂肪酸、分枝菌酸等细胞膜关键成分的合成。然而，哺乳动物宿主自身无法合成生物素，且血液中生物素浓度极低（约1 nM）。结核菌缺乏高亲和力的生物素转运蛋白，因此必须完全依赖自身的从头合成途径来获取这一“生命维生素”。这意味着，靶向该合成通路中的关键酶，有望实现对结核菌的选择性杀伤，而对人体细胞毒性极低。BioA正是该通路中催化7-酮-8-氨基壬酸生成7,8-二氨基壬酸的关键酶，是公认的潜力抗结核药物靶点。 二、 药物设计蓝图：从苗头化合物到先导化合物的理性优化之路 研究团队此前通过基于靶点的全细胞筛选，发现了一个具有N-芳基-N‘-苯甲酰哌嗪骨架的苗头化合物6，其靶点抑制活性（IC50）和抗菌活性（MIC50）俱佳，但药代动力学性质不佳，口服生物利用度低。通过对化合物6与BioA蛋白的共晶结构分析，研究人员明确了其结合模式，并以此为基础，对先导化合物36（对BioA的 IC50 = 75 nM，对Mtb的 MIC50 = 3.6 μM）展开了系统的构效关系研究和优化。 整个优化战役围绕分子的三个核心部分展开：苯并二氧戊环（R1）、哌嗪连接子、茚满酮（R2）。研究采用“拆解-优化-重组”的策略，对每个部分进行独立的结构修饰与活性评估，最终将最优片段组合，得到了最终的候选药物。 1. 优化战场一：苯并二氧戊环（R1）的“变形记” 最初的化合物36含有苯并二氧戊环结构，该结构可能存在代谢不稳定性。为此，团队合成了大量类似物（C1-C24），探索其替代物。 初步尝试遇挫：用环己烷（C1）、简单苯环（C2）或喹啉（C3）替换，导致活性完全丧失或大幅下降，表明该位置需要平面芳香结构以适配靶点的疏水口袋。 生物电子等排体探索：用苯并噻唑（C8）、苯并咪唑（C9）、苯并噁唑（C10）等杂环进行替换。其中，苯并噻唑C8表现最佳（IC50 = 140 nM， MIC50 = 8.4 μM），证明了杂环替代的可行性。 卤代苯环的突破：受早期活性化合物26（3-氯苯）的启发，系统研究了卤代苯环。发现间位取代优于对位和邻位。其中，3-溴苯类似物C13脱颖而出，活性显著提升（IC50 = 57 nM， MIC50 = 4.0 μM）。 氟原子的妙用：代谢稳定性的关键一跃：在C13的基础上，在苯环上引入氟原子，合成了3-溴-4-氟苯类似物C21。氟原子的引入不仅略微提升了生化活性（IC50 = 48 nM），更极大地改善了化合物的代谢稳定性。在后续的药代动力学研究中，C21展现了出色的口服暴露量和>100%的生物利用度，验证了“氟化策略”在优化药物性质上的成功。 2. 优化战场二：哌嗪连接子的“刚性测试” 团队尝试改变哌嗪连接子的构象和刚性，以探索其对活性的影响。 去除羰基（C25）或将其替换为硫代酰胺（C26）、磺酰胺（C27），均导致活性下降或丧失，证实了羰基对于维持与靶点的关键氢键相互作用至关重要。 增加柔性与刚性：合成同系物高哌嗪（C28） 或引入桥联哌嗪（C29）、螺环哌嗪（C30-C32） 等刚性生物电子等排体。这些改变均未带来活性提升，反而大多降低了效力。这表明初始苗头化合物中的哌嗪连接子构象已经过高度优化，其特定的扭曲构象对于将两端的药效团精准定位到靶点口袋中至关重要，不宜再做大的改动。 3. 优化战场三：茚满酮（R2）的“电子云改造” 这部分优化旨在增强该片段与靶点蛋白中色氨酸残基（Trp64）的 π-π堆积相互作用。 芳香性至关重要：用脂肪链（C33， C34）或单环芳香体系（C35， C36）替换茚满酮，活性完全丧失，验证了芳香环对维持相互作用的关键性。 引入氮原子，增强π-π堆积：受理论化学研究的启发，在茚满酮骨架中策略性地引入氮原子，以调节其电子云分布，从而增强与色氨酸的堆积作用。这一策略取得了巨大成功： 合成了一系列氮杂茚满酮类似物，如吡啶并类似物C43（IC50 = 47 nM， MIC50 = 1.2 μM）和C46（IC50 = 33 nM， MIC50 = 0.31 μM）。 分子建模揭示奥秘：对活性较差的C42和活性优异的C43进行分子模拟和量子化学计算发现，C42中氮原子与邻近羰基的电子排斥破坏了分子的平面性，导致π电子离域不均，削弱了与靶点的相互作用。而C43中氮原子的位置更优，保持了分子平面性和均匀的静电势分布，从而实现了更强的结合。 4. 终极组合：诞生明星化合物C47与C48 在分别获得最优的R1片段（3-溴-4-氟苯，来自C21）和最优的R2片段（特定氮杂茚满酮，来自C46）后，研究团队将这两个“王牌”片段组合，合成了最终的化合物C47和C48。 C48：将C21的酰基部分与C46的氮杂茚满酮部分通过优化的哌嗪连接子结合。C48不负众望，成为了整个系列中最强大的分子。 惊人的活性：其对Mtb BioA的解离常数Ki达到0.2 nM（皮摩尔级别），对野生型结核菌H37Rv的MIC50为0.093 μM。在对约50株临床分离株（包括敏感和耐药菌株）的测试中，C48的MIC范围在0.012至0.093 μM之间，展现出广谱且强效的抗菌活性。 共晶结构验证：C48与BioA的共晶结构显示，其结合由最优的形状互补性和三重π-π堆积相互作用驱动。3-溴-4-氟苯甲酰基部分与Tyr157和PLP辅因子形成三重堆积；哌嗪连接子被Tyr25和Phe402紧密包裹；而氮杂茚满酮则插入另一个口袋，与Trp64和Trp65形成平行的π-π堆积“三明治”结构。氮原子的引入，与羰基产生正协同效应，进一步放大了这种堆积相互作用的能量，从结构上解释了其超高活性的来源。 三、 药理与药代动力学概要：从体外到体内的卓越表现 靶点确认：通过使用BioA低表达和高表达的结核菌工程株进行测试，C48等活性化合物均表现出预期的活性变化趋势（对低表达菌株更敏感，对高表达菌株更耐药），确凿证明了其作用机制是通过抑制BioA靶点。 体外ADME性质优异：C48在人、小鼠肝微粒体及血浆中稳定性高，对hERG钾通道抑制弱（提示心脏毒性风险低），对主要人细胞色素P450酶无显著抑制（提示药物-药物相互作用风险低）。 出色的口服药代动力学：在小鼠模型中，C48展现出卓越的口服药代特性：高血药浓度-时间曲线下面积（AUC）、适中的半衰期、以及>100%的口服生物利用度。其口服给药后的AUC与MIC的比值（AUC/MIC）高达1570，相较于最初的苗头化合物6，提升了惊人的39,000倍，预示着强大的体内杀菌潜力。 低细胞毒性：在HepG2细胞系中，C48在高达100 μM浓度下未显示细胞毒性，证明了其良好的安全性窗口。 体内疗效验证：在能更好模拟人体低生物素生理环境的小鼠感染模型中，口服给予C48能显著降低小鼠肺部和脾脏的细菌负荷（分别降低1.0和2.1个log10 CFU），首次在体内确证了生物素合成通路作为抗结核药物靶点的可行性。 四、 总结与展望 这项研究不仅成功开发出了C48这一极具前景的抗结核候选药物，更完整展示了一个基于结构的理性药物设计成功案例。通过系统地优化分子的三个药效团，并巧妙运用引入氟原子改善代谢、减少可旋转键、及引入氮原子增强π-π堆积等策略，将活性从微摩尔提升至纳摩尔甚至皮摩尔级别，同时极大地优化了类药性和药代动力学性质。C48的强效、广谱（包括对耐药菌）、口服有效及卓越的安全性，使其成为对抗结核病，特别是耐药结核病的有力新武器候选。这项成果也为针对其他病原体必需代谢通路的新药研发提供了宝贵的策略和思路。 原文链接： https://doi.org/10.1021/acs.jmedchem.5c03325 （如需文献PDF，点击关注，后台私信） 声明本文内容基于公开发表的学术论文整理，仅供参考交流。著作权归原作者和出版集团所有，欢迎合理转载，请注明来源【MedChem Reader】。文献详细全面信息请跳转原文阅读。投稿，合作，交流请后台联系。 往期推荐 →【JMC】抗癌免疫新星：Incyte团队报道新型强效双靶点DGKα/ζ抑制剂INCB191358的发现 →【JMC】华理团队报道：高选择性S1PR1激动剂TYY-31，溃疡性结肠炎治疗新星诞生 →【JMC】天津大学团队开发靶向LAT1的新型鬼臼毒素衍生物B11，抗癌效力倍增，安全性提升四倍以上 【关注我们，一起探索科学前沿】👍 您的每一次【点赞】【转发】【】，都是我们持续创作优质内容的动力！

The randomized Phase 2b ASPIRE trial successfully completed planned enrollment of over 360 patients, reflecting strong execution and robust site engagement ASPIRE is designed to assess the effect of buloxibutid on forced vital capacity (FVC) over 52 weeks, the regulatory endpoint for idiopathic pulmonary fibrosis (IPF) Topline results are expected in mid-2027, supported by cash runway into the second half of 2028 STOCKHOLM, SE / ACCESS Newswire / April 22, 2026 / Vicore Pharma Holding AB (Nasdaq Stockholm:VICO), unlocking the potential of a novel class of drugs, angiotensin II type 2 receptor agonists (ATRAGs), today announced completion of enrollment in the global Phase 2b ASPIRE trial evaluating buloxibutid for the treatment of IPF. The ASPIRE trial successfully enrolled more than 360 patients across over 100 sites in 14 countries, including 29 sites in the United States. Full trial enrollment was achieved earlier than anticipated, reflecting strong interest in buloxibutid and efficient trial execution. "Completing enrollment in ASPIRE represents an important milestone for Vicore and the buloxibutid program," said Ahmed Mousa, Chief Executive Officer of Vicore. "We are encouraged by the excellent collaboration with dedicated sites and the high level of interest from investigators and patients globally, which enabled efficient recruitment ahead of our expectations. This level of engagement reflects both the significant unmet need in IPF and the desire for new therapies. With enrollment complete, our focus is on continued disciplined execution as we advance toward a topline data readout in mid-2027." IPF remains a progressive and fatal lung disease with significant unmet medical need. Currently approved therapies have been shown to slow lung function decline, but the magnitude of benefit is limited, and treatment is frequently associated with tolerability challenges, underscoring the need for additional therapeutic options. "IPF remains a serious and progressive disease with limited treatment options," said Toby Maher, MD, PhD, Professor of Clinical Medicine and Director of Interstitial Lung Disease at Keck Medicine of Southern California. "With enrollment in ASPIRE complete, I'm looking forward to the trial's results and continue to be optimistic about buloxibutid's potential to help address this persistent unmet medical need." ASPIRE is a randomized, placebo-controlled, 52-week Phase 2b trial evaluating two doses of buloxibutid both as monotherapy and on top of background standard of care. The trial will measure the impact of buloxibutid on FVC over the 52-week treatment period, the regulatory endpoint for IPF. ASPIRE builds on encouraging results from Vicore's Phase 2a AIR trial in which buloxibutid treatment was associated with an improvement in FVC over 36 weeks. Vicore expects to report topline results from ASPIRE in mid-2027 and is well positioned to execute the program with cash runway extending into the second half of 2028. Vicore sincerely thanks the patients participating in the ASPIRE trial, as well as their families and caregivers, and the investigators, study staff, and clinical trial sites whose commitment and collaboration made this milestone possible. For more information, please contact: Megan Richards, VP, IR & Comms, +1 978 269 4372, megan.richards@vicorepharma.com Hans Jeppsson, CFO, +46 70 553 14 65, hans.jeppsson@vicorepharma.com About Vicore Pharma Vicore Pharma is a clinical-stage biopharmaceutical company unlocking the potential of a new class of drugs with disease-modifying potential in respiratory and fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). The company's lead program, buloxibutid, is a first-in-class oral small molecule angiotensin II type 2 receptor agonist, which has received Orphan Drug and Fast Track designation from the United States Food and Drug Administration and is currently being investigated in the global 52-week Phase 2b ASPIRE trial in IPF. Vicore is publicly listed on the Nasdaq Stockholm exchange with the ticker VICO. About Idiopathic Pulmonary Fibrosis (IPF) IPF is a progressive fibrotic lung disease, impacting approximately 3 million people globally. The average life expectancy following diagnosis is 3-5 years, and currently approved therapies offer only modest slowing of disease progression. While there are three anti-fibrotic therapies available today, a large proportion of patients do not initiate treatment, and those who do often discontinue due to limited efficacy and significant tolerability issues. With a growing patient population, there is a clear need for new treatments. About the Phase 2b ASPIRE Trial ASPIRE (NCT06588686) is a global 52-week Phase 2b, randomized, double-blind, placebo-controlled clinical trial designed to assess the efficacy and safety of buloxibutid in IPF patients who are either not currently on treatment or receiving background standard of care. Participants are randomized to receive one of two doses of buloxibutid (100 mg or 50 mg taken orally twice daily) or placebo. The primary endpoint is change from baseline in forced vital capacity (FVC) at 52 weeks, the registrational endpoint for IPF. Secondary endpoints include safety, tolerability, and the proportion of patients with disease progression over the trial period. The trial enrolled over 360 patients from more than 100 sites across 14 countries, including the United States. Attachments Vicore Pharma Completes Enrollment in the Phase 2b ASPIRE Trial of Buloxibutid in Idiopathic Pulmonary Fibrosis SOURCE: Vicore Pharma Holding View the original press release on ACCESS Newswire