S1PR3

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。

Initiated Single-Ascending Dose (SAD) Phase 1 clinical study evaluating LP659 LA JOLLA, Calif.--(BUSINESS WIRE)-- Longboard Pharmaceuticals, Inc. (Nasdaq: LBPH), a clinical-stage biopharmaceutical company focused on developing novel, transformative medicines for neurological diseases, today announced the initiation of a Phase 1 randomized, double-blind, placebo-controlled, SAD clinical study of LP659. LP659 is an oral, centrally acting, next-generation sphingosine-1-phosphate (S1P) receptor subtypes 1 and 5 modulator in development for the potential treatment of rare neuroinflammatory conditions. “Expanding our potentially best-in-class clinical-stage pipeline with LP659 is very exciting. We founded Longboard to leverage Arena’s successful record of discovering and developing molecules with differentiated pharmacokinetics, pharmacodynamics and receptor engagement, which we believe has been validated again by the recent approval of etrasimod, an S1P receptor modulator. LP659 was designed by the same team as etrasimod with the goal of creating a next-generation, brain penetrant S1P receptor modulator while preserving its unique qualities, including avoiding activity at S1P2 and S1P3 receptor subtypes which have been associated with serious adverse events. We plan to share Phase 1 SAD data and additional clinical plans for LP659 in the first half of 2024,” stated Kevin R. Lind, Longboard’s President and Chief Executive Officer. About the Phase 1 SAD Clinical Study The primary objective of this Phase 1 randomized, double-blind, placebo-controlled, single-ascending dose clinical study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of LP659 in up to 48 healthy adult volunteers. About LP659 LP659 is an oral, centrally acting, next-generation S1P receptor subtypes 1 and 5 (S1P1,5) modulator in development for rare neuroinflammatory conditions. Aberrant modulation of the S1P receptor has been shown to be involved in a wide range of neurological diseases. LP659 avoids S1P2,3 which may be associated with off-target adverse events. We believe LP659’s potential selectivity and specificity could result in a superior pro the clinic compared to drugs that may not fully engage the intended GPCR target, may cause off-target activity, or may be associated with other undesirable effects. ABOUT LONGBOARD PHARMACEUTICALS Longboard Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company focused on developing novel, transformative medicines for neurological diseases. Longboard is working to advance a portfolio of centrally acting product candidates designed to be highly selective for specific G protein-coupled receptors (GPCRs). Longboard’s small molecule product candidates are based on more than 20 years of GPCR research. Longboard is evaluating LP352, an oral, centrally acting 5-hydroxytryptamine 2C (5-HT2C) receptor superagonist, with no observed impact on 5-HT2B and 5-HT2A receptor subtypes. LP352 is currently in a Phase 1b/2a clinical trial, the PACIFIC Study, evaluating participants ages 12 to 65 years old with a broad range of Developmental and Epileptic Encephalopathies (DEEs), including Lennox-Gastaut syndrome, Dravet syndrome and other DEEs. Enrollment was completed in the summer of 2023, and topline data are expected in January 2024. Longboard is also evaluating LP659, an oral, centrally acting, next-generation sphingosine-1-phosphate (S1P) receptor subtypes 1 and 5 modulator, which is in development for the potential treatment of rare neuroinflammatory conditions in a Phase 1 single-ascending dose (SAD) clinical trial in healthy volunteers. FORWARD-LOOKING STATEMENTS Certain statements in this press release are forward-looking statements that involve a number of risks and uncertainties. In some cases, you can identify forward-looking statements by words such as “focus”, “in development for”, “potential”, “believe”, “goal”, “plan”, “first half of 2024”, “objective”, “may”, “could”, “working to”, “designed to”, “expect”, “January 2024”, “later this year”, or the negative, plural or other tenses of these words or other comparable language, and they may include, without limitation, statements about the following: the vesting of stock options; continued employment of newly hired Longboard employees; Longboard’s clinical and preclinical product candidates and programs, including their advancement, timing of initiation and completion of clinical trials, timing of topline data from clinical trials, characteristics of clinical trial participants, plans for future clinical trials, their potential (including to be highly selective, have differentiated pharmacokinetics, pharmacodynamics and receptor engagement, have unique qualities associated with other compounds, have a superior profile, and the numbers and types of conditions they may address), and their design and characteristics; Longboard’s ability to develop product candidates and deliver medicines; and Longboard’s focus and work. For such statements, Longboard claims the protection of the Private Securities Litigation Reform Act of 1995. Actual events or results may differ materially from Longboard’s expectations. Factors that could cause actual results to differ materially from those stated or implied by Longboard’s forward-looking statements include, but are not limited to, the following: risks related to Longboard’s limited operating history, financial position and need for additional capital; Longboard will need additional managerial and financial resources to advance all of its programs, and you and others may not agree with the manner Longboard allocates its resources; risks related to the development and commercialization of Longboard’s product candidates; Longboard’s product candidates are in the early phases of a lengthy research and development process, the timing, manner and outcome of research, development and regulatory review is uncertain, and Longboard’s product candidates may not advance in research or development or be approved for marketing; enrolling participants in Longboard’s ongoing and intended clinical trials is competitive and challenging; PACIFIC Study participants’ diagnoses are as of time of screening and are subject to change; macroeconomic events stemming from the COVID-19 pandemic or evolving geopolitical developments such as the conflicts in Ukraine and the Middle East, including but not limited to the impact on Longboard’s clinical trials and operations, the operations of Longboard’s suppliers, partners, collaborators, and licensees, and capital markets, which in each case remains uncertain; risks related to unexpected or unfavorable new data; nonclinical and clinical data is voluminous and detailed, and regulatory agencies may interpret or weigh the importance of data differently and reach different conclusions than Longboard or others, request additional information, have additional recommendations or change their guidance or requirements before or after approval; results of clinical trials and other studies are subject to different interpretations and may not be predictive of future results; topline data may not accurately reflect the complete results of a particular study or trial; risks related to relying on licenses or collaborative arrangements; other risks related to Longboard’s dependence on third parties; competition; product liability or other litigation or disagreements with others; government and third-party payor actions, including relating to reimbursement and pricing; risks related to regulatory compliance; and risks related to Longboard’s and third parties’ intellectual property rights. Additional factors that could cause actual results to differ materially from those stated or implied by Longboard’s forward-looking statements are disclosed in Longboard’s filings with the Securities and Exchange Commission (SEC). These forward-looking statements represent Longboard’s judgment as of the time of this release. Longboard disclaims any intent or obligation to update these forward-looking statements, other than as may be required under applicable law.