TRKA

— Oral presentation at the European Lung Cancer Congress 2024 of Phase IIIb data demonstrating median PFS of 13.7 months and median OS not reached in treatment-naïve patients — — If approved, would confirm 2021 conditional approval and expand indication to more patients — HONG KONG and SHANGHAI, China and FLORHAM PARK, N.J., March 27, 2024 (GLOBE NEWSWIRE) -- HUTCHMED (China) Limited (“HUTCHMED”) (Nasdaq/AIM:​HCM; HKEX:​13) today announces that the supplemental New Drug Application (“sNDA”) for savolitinib, in adult patients with locally advanced or metastatic non-small cell lung cancer (“NSCLC”) with mesenchymal epithelial transition factor (“MET”) exon 14 skipping alteration, has been accepted for review by the China National Medical Products Administration (NMPA). If approved, the new label indication for savolitinib will be expanded to include treatment-naïve patients in China. Savolitinib was previously granted conditional approval in China for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. Savolitinib was launched and is marketed under the brand name ORPATHYS® by our partner, AstraZeneca for this patient population, representing the first selective MET inhibitor approved in China. More than a third of the world’s lung cancer patients are in China and, among those with NSCLC globally, approximately 2-3% have tumors with MET exon 14 skipping alterations. Preliminary efficacy and safety data from the first-line cohort of the confirmatory Phase IIIb clinical trial (NCT04923945) were presented during the IASLC World Conference on Lung Cancer (WCLC) in September 2023. Final data from the confirmatory Phase IIIb trial were presented at the European Lung Cancer Congress on March 20, 2024. The data from this study provide confirmatory evidence for savolitinib as a targeted treatment option for treatment-naïve or previously treated patients with MET exon 14 skipping alteration NSCLC. In treatment-naïve patients, objective response rate (“ORR”) was 62.1% (95% CI: 51.0% to 72.3%), disease control rate (“DCR”) was 92.0% (95% CI: 84.1% to 96.7%) and median duration of response (“DoR”) was 12.5 months (95% CI: 8.3 months to 15.2 months), as assessed by an independent review committee. Median progression free survival (“PFS”) was 13.7 months (95% CI: 8.5 months to 16.6 months) and median overall survival (“OS”) was not reached with median follow-up of 20.8 months. In previously treated patients, ORR was 39.2% (95% CI: 28.4% to 50.9%), DCR was 92.4% (95% CI: 84.2% to 97.2%) and median DoR was 11.1 months (95% CI: 6.6 months to not reached), as assessed by an independent review committee. Median PFS was 11.0 months (95% CI: 8.3 months to 16.6 months) and median OS was not mature with median follow-up of 12.5 months. Responses occurred early (time to response 1.4-1.6 months) in both treatment-naïve and previously treated patients. The safety profile was tolerable and no new safety signals were observed. The most common drug-related treatment-emergent adverse events of Grade 3 or above (5% or more of patients) were abnormal hepatic function (16.9%), increased alanine aminotransferase (14.5%), increased aspartate aminotransferase (12.0%), peripheral oedema (6.0%) and increased gamma-glutamyltransferase (6.0%). About NSCLC and MET aberrations Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.2 The majority of NSCLC patients (approximately 75%) are diagnosed with advanced disease, and approximately 10-15% of NSCLC patients in the U.S. and Europe and 30-40% of patients in Asia have EGFRm NSCLC. 3,4,5,6 MET is a tyrosine kinase receptor that has an essential role in normal cell development.7 MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is one of the mechanisms of acquired resistance to EGFR TKIs for metastatic EGFR-mutated NSCLC.7,8 Approximately 2-3% of NSCLC patients have tumors with MET exon 14 skipping alterations, a targetable mutation in the MET gene.9 Among patients who experience disease progression post-osimertinib treatment, approximately 15-50% present with MET aberration.10,11,12,13,14 The prevalence of MET depends on the sample type, detection method and assay cut-off used.15 About Savolitinib (ORPATHYS® in China) Savolitinib is an oral, potent and highly selective MET tyrosine kinase inhibitor that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression. Savolitinib is marketed in China under the brand name ORPATHYS® for the treatment of patients with non-small cell lung cancer with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. It is currently under clinical development for multiple tumor types, including lung, kidney and gastric cancers, as a single treatment and in combination with other medicines. Starting on March 1, 2023, ORPATHYS® was included in the National Reimbursement Drug List (NRDL) for the treatment of locally advanced or metastatic NSCLC adult patients with MET exon 14-skipping alterations who have progressed after or unable to tolerate platinum-based chemotherapy. In 2011, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize savolitinib. Joint development of savolitinib in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of savolitinib in China. AstraZeneca is responsible for the commercialization of savolitinib in China and worldwide. Sales of savolitinib are recognized by AstraZeneca. About HUTCHMED HUTCHMED (Nasdaq/AIM:​HCM; HKEX:​13) is an innovative, commercial-stage, biopharmaceutical company. It is committed to the discovery, global development and commercialization of targeted therapies and immunotherapies for the treatment of cancer and immunological diseases. It has approximately 5,000 personnel across all its companies, at the center of which is a team of about 1,800 in oncology/immunology. Since inception, HUTCHMED has focused on bringing cancer drug candidates from in-house discovery to patients around the world, with its first three medicines marketed in China, the first of which is also marketed in the U.S. For more information, please visit: www.hutch-med.com or follow us on LinkedIn. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect HUTCHMED’s current expectations regarding future events, including its expectations regarding the therapeutic potential of savolitinib, the further clinical development for savolitinib, its expectations as to whether any studies on savolitinib would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates and the timing and availability of subjects meeting a study’s inclusion and exclusion criteria; changes to clinical protocols or regulatory requirements; unexpected adverse events or safety issues; the ability of savolitinib, including as a combination therapy, to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions and to gain commercial acceptance after obtaining regulatory approval; the potential market of savolitinib for a targeted indication; and the sufficiency of funding. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see HUTCHMED’s filings with the U.S. Securities and Exchange Commission, The Stock Exchange of Hong Kong Limited and on AIM. HUTCHMED undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise. Medical Information This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. CONTACTS Investor Enquiries+852 2121 8200 / ir@hutch-med.com Media Enquiries Ben Atwell / Alex Shaw, FTI Consulting+44 20 3727 1030 / +44 7771 913 902 (Mobile) / +44 7779 545 055 (Mobile) / HUTCHMED@fticonsulting.comZhou Yi, Brunswick+852 9783 6894 (Mobile) / HUTCHMED@brunswickgroup.com Nominated Advisor Atholl Tweedie / Freddy Crossley / Daphne Zhang, Panmure Gordon+44 (20) 7886 2500 ____________________REFERENCES1World Health Organization. International Agency for Research on Cancer. All cancers fact sheet. Available at: https://gco.iarc.fr/today/­data/factsheets/cancers/39-All-cancers-fact-sheet.pdf. Accessed November 2022.2American Cancer Society. What is Lung Cancer? Available at: https://www.cancer.org/cancer/lung-cancer/about/what-is.html. Accessed November 2022.3Knight SB, et al. Progress and prospects of early detection in lung cancer. Open Biol. 2017;7(9): 170070.4Keedy VL, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients with Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 2011:29;2121-27.5Zhang Y, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48).6Szumera-Ciećkiewicz A, et al. EGFR Mutation Testing on Cytological and Histological Samples in 11. Non-Small Cell Lung Cancer: a Polish, Single Institution Study and Systematic Review of European Incidence. Int J Clin Exp Pathol. 2013:6;2800-12.7Uchikawa E, et al. Structural basis of the activation of c-MET receptor. Nat Commun. 2021;12(4074).8Wang Q, et al. MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer. Journal of Hematology & Oncology. 2019;63.9Vuong HG, et al. Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer – A systematic review and meta-analysis. Lung Cancer 2018; 123: 76-82.10Soria JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113-125.11Mok TS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017;376(7):629-640.12Hartmaier R, et al. Tumor genomics in patients (pts) with advanced epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib therapy in the Phase II ORCHARD study. Cancer Res 15 June 2022; 82 (12_Supplement): LB078.13Piotrowska, et al. MET amplification (amp) as a resistance mechanism to osimertinib. Journal of Clinical Oncology 2017 35:15_suppl, 9020-9020. 14Hartmaier, et al. Detection of MET-mediated EGFR tyrosine kinase inhibitor (TKI) resistance in advanced non-small cell lung cancer (NSCLC): biomarker analysis of the TATTON study. Cancer Res (2019) 79 (13_Supplement): 4897.15Coleman N, et al. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open. 2019;6(6).

咨询合作     药物筛选中心（暨南大学），隶属于暨南大学药学院公共科研平台。中心拥有Echo550微量液体超声转移工作站等先进的自动化药物筛选仪器，前期支撑的多个激酶抑制剂已经产业转化及发表JMC等高水平论文。目前，筛选中心建有激酶、蛋白酶、HDAC、病毒、细菌等筛选模型，能够开展肿瘤、病毒和细菌感染性疾病等领域相关靶标、细胞、机制的筛选和研究，每天能够完成数万次的新药筛选反应。已建立的药物筛选模型1）激酶：Abl, ABL(M351T), ABL(H396P), ABL(Y253F), ABL1 (E255K), ABL1 (G250E), ABL(Q252H), AKT1, AKT2, AKT3, ALK, ALK5, AuroraA, AuroraB, AXL, BRAF, BRAF(V599E), BTK, DDR1, DDR2, EGFR, EGFR (T790M), EGFR(L858R), EGFR(L861Q), EGFR(T790ML858R), EGFR(D746-750), EGFR(D746-750/T790M), Flt3, FLT3(D835Y), FGFR1, FGFR2, FGFR3, FGFR4, Her2, Her4, KIT, MET, IGF-1R, FGFR1, JAK1, JAK2, JAK3, MAPK10, MAPK14, mTOR, TrkA, TrkB, TrkC,TYK2, KDR, SRC, PDGFRa, PDGFRA(D842V), PDGFRb, RET, ZAK……2）肿瘤细胞模型：近500种肿瘤细胞系和基于Ba/F3的耐药模型。细胞系模型（300种）包括肺癌、胰腺癌、胃癌、肝癌、白血病等肿瘤；Ba/F3模型（200种）包括ABL、EGFR、FGFR、RET、ALK、FLT3、KIT、KRAS等靶点的敏感和耐药模型（支持了5个分子进入临床研究）。3）肿瘤移植瘤模型对外服务1）蛋白和细胞活性；2）体内抗肿瘤药效；3）蛋白表达、小分子-蛋白共晶；4）药代动力学；5）基于化学蛋白质组学的靶标发现;6) 肿瘤靶标及其候选药物的成药性评估。     咨询合作

笔者根据美国FDA官网的公开信息，解读2023年获FDA药物评估和研究中心（CDER）批准上市的小分子药物，并总结了每个药物的分子结构、靶点/机制、研发公司，制作成图表。以下文字内容大多参考自FDA官方的药物说明书和分子结构图底下的参考资料。部分的数据除非特别引用，一般是参考维基百科和药企官方公告。小分子药物结构、机制与适应症汇总此前已介绍了上半年获批的小分子药物，请查看这篇文章：【一图看懂】2023上半年获FDA批准的小分子新药及药物设计思路10/12/2023: Velsipity (etrasimod)基本信息：Etrasimod是由Pfizer开发的1-磷酸鞘氨醇（S1P）受体调节剂，以高亲和力与S1P受体1、4和5结合，用于治疗成人中重度活动性溃疡性结肠炎（UC）。Etrasimod部分地、可逆地阻断淋巴细胞从淋巴器官流出的能力，减少外周血中淋巴细胞的数量。UC是一种自身免疫性疾病，影响北美和欧洲约380万人，症状包括出血和慢性腹泻、腹痛和失禁等。分子设计思路：首先通过内部HTS确定磺酰胺1是S1P1受体（EC50 = 6.7 nM）的有效激动剂。但芳基磺酰胺类似物在口服给药后不能有效降低小鼠的淋巴细胞计数。分别用吲唑和1,2,4-恶二唑取代苯环和磺酰胺，得到体内potency提高的分子2。随后，i）在吲唑环上引入酸性侧链，模拟S1P中发现的磷酸盐残基；ii）用二氢吲哚替换吲唑类环；iii）用氰基替换苯环的其中一个三氟甲氧基，发现二氢吲哚3在淋巴细胞降低实验中产生最大反应，将其作为lead。3对心脏表达的S1P3亚型的选择性（S1P3的激动会导致啮齿类动物心动过缓）非常好，且半衰期相对上市药物Fingolimod缩短明显（长达6-9天，停药后外周淋巴细胞水平恢复正常需要1-2个月），符合最初的优化目标。遗憾的是静脉输注24小时后，在大鼠大脑和脑脊液中检测不到4。提高CNS渗透性（可通过直接作用于星形胶质细胞上表达的S1P1来减少神经炎症）是进一步优化的重点。用甲氧基替换1,2,4-恶二唑linker，并对苯环的取代基进行优化得到上市药物Etrasimod，其相对于4得到改善的CNS暴露，脑-血浆（B/P）比率为1.9。图1. Etrasimod的药物设计。10/26/2023: Agamree (vamorolone)基本信息：Vamorolone是由Santhera开发的是糖皮质激素受体的部分激动剂（皮质类固醇），用于治疗2岁及以上的杜氏肌营养不良症 (DMD) 患者。美国的DMD患者约有11,000-13,000人，目前的标准治疗是皮质类固醇（尽管其存在严重的不良事件），大约70%的患者同时接受皮质类固醇治疗。DMD是最常见的肌营养不良症，是一种X连锁隐性遗传病（几乎只影响男性），其特征是DMD基因（人类基因组中最大的基因）发生突变，并且编码的肌营养不良蛋白丢失。DMD的特点是肌肉功能退化。患有这种罕见的致命疾病的患者会慢慢失去行走能力并出现呼吸衰竭，平均预期寿命低于30岁。分子设计思路：Vamorolone显然是皮质醇（氢化可的松）和泼尼松龙（1,2-脱氢皮质醇）的衍生物，结构上少了羟基，多了双键和甲基。Vamorolone多出来的双键已被证明可以去除与糖皮质激素受体的分子接触位点，并导致“解离”特性，即反式激活活性相对丧失，但保留反式抑制活性。反式激活引发了GR介导的药物活性的许多安全问题，而反式抑制则提高了抗炎功效。图2. Vamorolone的药物设计。11/8/2023: Fruzaqla (fruquintinib)基本信息： Fruquintinib（呋喹替尼）是由和黄医药开发（2023年1月以11.3亿美元授权给武田制药）的一款口服的高选择性、强效的VEGFR-1/2/3（IC50分别为33、35和0.5 nM，对其它激酶选择性较好）抑制剂，用于治疗既往接受过氟嘧啶、奥沙利铂和伊立替康治疗的转移性结直肠癌患者，包括既往接受过抗VEGF治疗和/或抗EGFR治疗（RAS野生型）的患者。在美国，2023年将诊断出约153,000例新发CRC病例，占所有新发癌症病例的7.8%。大约70%的CRC患者无论是在诊断时还是治疗后都会出现转移性疾病。分子设计思路：此前已有多款VEGFR抑制剂上市，其中市场表现最好的是Lenvatinib。如图3所示，呋喹替尼和Lenvatinib还是有不少相似之处。呋喹替尼主要改动的地方在杂环上多了一个N，以及用呋喃环替换了苯环上原有的极性侧链。图3. 部分上市的VEGFR抑制剂。11/15/2023: Defencath (taurolidine, heparin)基本信息：Defencath是由CorMedix开发的是牛磺罗定（taurolidine，噻二嗪类抗菌剂）和肝素（抗凝剂）的组合，用于降低通过中心静脉导管（CVC）接受血液透析 (HD) 的成年肾衰竭患者导管相关血流感染 (CRBSI) 的发生率。CRBSI在CVC患者中很常见。大约80%开始血液透析的患者将插入CVC以建立血管通路。每年使用CVC等血管内装置的患者会发生约250,000例CRBSI，导致约1/4的感染患者死亡。血液透析中的 CRBSI由多种病原体引起，其中许多病原体具有抗生素耐药性。分子设计思路：没找到牛磺罗定的药物发现文章。牛磺罗定源自内源性氨基酸衍生物牛磺酸。牛磺罗定在体内代谢为牛磺酸酰胺，最终生成牛磺酸和水，释放羟甲基，与细菌细胞壁中的胞壁蛋白以及内毒素和外毒素的氨基和羟基发生化学反应。该反应使细菌细胞壁的内毒素以及复杂的多糖和脂多糖成分变性，并使敏感的外毒素失活。图4. 牛磺罗定的抗菌机制。来源：PLoS ONE 2010, 5(1): e8927.11/15/2023: Augtyro (repotrectinib)基本信息：Repotrectinib是由BMS开发（2022年41亿美元收购Turning Point获得）的酪氨酸蛋白激酶（ROS1）抑制剂，用于治疗局部晚期或转移性ROS1阳性NSCLC成年患者。Repotrectinib是原癌基因ROS1和TRKA、TRKB和TRKC的抑制剂。包含ROS1结构域的融合蛋白可以通过下游信号通路的过度激活来驱动致瘤潜力，从而导致不受限制的细胞增殖。ROS1融合发生在约1-2%的NSCLC患者中。ROS1阳性肿瘤患者的平均年龄为50岁，往往比普通肺癌患者更年轻，其中女性多于男性，并且可能几乎没有吸烟史。ROS1阳性肺癌往往具有侵袭性，通常可扩散至大脑。分子设计思路：由于TRK激酶结构域的二次突变，总是会产生获得性耐药。TRKA中最常见的突变为G595R和G667C，分子模型表明， G595R突变引入了larotrectinib羟基吡咯烷基团的空间位阻（图5）。同样， G667C突变增加了larotrectinib的二氟苯基的空间位阻。为了克服上述耐药突变，开发了两种大环化合物LOXO-195和TPX-0005（即Repotrectinib），与larotrectinib的骨架相比，引入更大的构象刚性，并避免与R595和C667的空间clash。图5. Repotrectinib的药物设计。来源：J. Med. Chem. 2020, 63, 10726–10741.11/16/2023: Truqap (capivasertib)基本信息：Capivasertib是由阿斯利康开发的丝氨酸/苏氨酸激酶AKT（AKT1-3）的ATP竞争性抑制剂，与氟维司群联合用于治疗患有激素受体（HR）阳性、HER2阴性、患有一种或多种PIK3CA/AKT1/PTEN改变的局部晚期或转移性乳腺癌成年患者。PI3K-Akt-mTOR通路是人类癌症中最常失调的信号通路之一，已被证明可以介导对细胞毒性、抗激素和靶向治疗的耐药性。Akt是该信号通路中的关键节点。2020年，全球有超过200万患者被诊断患有乳腺癌，近685,000 死亡。HR阳性乳腺癌是最常见的乳腺癌亚型，超过65%的肿瘤是HR阳性且HER2低或阴性。PIK3CA、AKT1和PTEN突变影响高达50%的晚期HR阳性乳腺癌患者。分子设计思路：高通量的fragment虚拟筛选将氮杂吲哚1鉴定为PKB（即Akt）的ATP竞争性配体。该片段通过SBDD优化为6-苯基嘌呤2。用哌啶取代2中的苯基并引入4-氨基得到3（碱性胺与Glu和Asn分别形成盐桥和氢键）。为了与P-loop的亲脂口袋相互作用，引入芳香族基团，得到氯苯基取代的分子4。当用4-氯苄基替换4-氯苯基，得到的分子5对PKA的选择性提高至约30倍。但5具有高体内清除率和低口服生物利用度，需要进一步优化。尝试了不同位置的SAR，发现通过简单地在5的4-氨基哌啶引入4-酰胺（调整了pKa/溶解度），即可得到PK显著提高的分子6。然而，分子6对ROCK2激酶的选择性仅为5倍（ROCK2抑制剂已被证明可显著降低血压并导致心率和心肌收缩力增加），且对hERG的IC50达到5 μM。突破点在于苄基的α-碳取代，首先用碱性侧链取代，发现携带碱性基团的侧链会导致高清除率和低口服生物利用度；随后引入的中性尤其是含羟基（改善hERG抑制活性的常见策略）的侧链则显著提高了对ROCK2和hERG的选择性，最终得到上市药物Capivasertib。图6. Capivasertib的药物设计。11/27/2023: Ogsiveo (nirogacestat)基本信息：nirogacestat是由SpringWorks Therapeutics开发的口服γ分泌酶抑制剂，用于治疗需要全身治疗的进展性硬纤维瘤成年患者。硬纤维瘤是局部侵袭性和侵袭性软组织肿瘤，可导致严重的发病率。此外，当重要结构受到影响时，硬纤维瘤可能会危及生命。虽然硬纤维瘤不会转移，但现有的超适应症全身治疗通常难以治愈，并且手术切除后复发率高达77%。分子设计思路：没找到nirogacestat的药物发现文章。查阅文献nirogacestat应该是参考二肽类似物DAPT（Aβ IC50 = 20 nM）优化而来。图7.nirogacestat的药物设计。12/5/2023: Fabhalta (iptacopan)基本信息：旁路途径（AP）是补体激活的放大环，是各种人类疾病的促成因素，包括年龄相关性黄斑变性（AMD），阵发性睡眠性血红蛋白尿（PNH）等。AP的补体系统成分包括蛋白酶因子B (FB)和蛋白酶因子D (FD)等。FB是一种类胰蛋白酶丝氨酸蛋白酶，主要在肝脏和巨噬细胞产生，以潜伏形式在人体血液中循环。通过抑制FB可以阻断AP放大循环，用于治疗多种补体介导的疾病。Iptacopan是由诺华研发的FB抑制剂，用于治疗PNH。Iptacopan与补体旁路途径的FB结合，调节C3的裂解、下游效应子的产生以及末端途径的扩增。在PNH中，血管内溶血 (IVH) 由下游膜攻击复合物 (MAC) 介导，而血管外溶血 (EVH) 由C3b调理作用促进。Iptacopan在补体级联的替代途径中发挥近端作用，控制C3b介导的EVH和末端补体介导的IVH。分子设计思路：通过高通量筛选鉴定出氨基咪唑啉1（IC50 = 6.6 μM，SPR Kd = 10 μM)片段。考虑到萘环骨架不容易进行SAR，且萘基的非极性性质可能会使与相对极性的S1口袋很难产生positive的相互作用，用相对极性的吲哚环取代萘环。同时，用不同碱度的胺来替换咪唑啉，发现哌啶衍生物18的IC50为50 μM。18的结构简单（MW = 242.4），加上哌啶的C-2和C-4方便衍生化，从而提供新的SAR位点：1）在哌啶的2位引入苯基得到化合物19，其共晶结构显示哌啶的C-4位能够生长到S3口袋中；2）在哌啶的C-4位引入-OMe得到的21可以显著提高效力，还表现出α2c受体结合亲和力的显著降低 (IC50 = 11 μM)。值得一提的是，当21的苯基换为羟基，得到的哌啶29相比21效力提高了2倍。29与FB的共晶揭示了羟基和结晶缓冲液中的硫酸根离子之间的相互作用，与Arg192、Val218和Asn220B形成了复杂的氢键网络。为了进一步提高potency，尝试通过在哌啶的C-2位置引入极性官能团来模拟这种相互作用。重新评估了29和19与FB结合的晶体结构，发现19中苯环的对位位置完美，可以将取代基放入硫酸盐占据的空间中。在苯环对位连上羧酸，得到的35相比29的potency提高了近100倍。此外，酸的添加消除了hERG和肾上腺素能受体活性，但35在不同物种间存在功能活性差异。猜测填充S3口袋应该会增强对抗人类酶的效力，也可能导致小鼠效力随之增加。最后，在哌啶的C-4处用乙氧基替换甲氧基能更深地扩展到S3口袋，用吲哚C-5甲氧基替换甲基提供了更大程度的眼部AP抑制，最终得到上市药物iptacopan。图8. Iptacopan的药物设计。