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Article(id=1201124479209533493, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0082, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1706198400000, receivedDateStr=2024-01-26, revisedDate=1706630400000, revisedDateStr=2024-01-31, acceptedDate=null, acceptedDateStr=null, onlineDate=1764299991656, onlineDateStr=2025-11-28, pubDate=1710172800000, pubDateStr=2024-03-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764299991656, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764299991656, creator=13701087609, updateTime=1764299991656, updator=13701087609, issue=Issue{id=1201124478286786612, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='3', pageStart='493', pageEnd='788', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764299991434, creator=13701087609, updateTime=1764300490467, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201126571420639892, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201126571420639893, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=493, endPage=502, ext={EN=ArticleExt(id=1201124479498940473, articleId=1201124479209533493, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=First-in-class small molecule drugs in 2023, columnId=1190335349059588909, journalTitle=Acta Pharmaceutica Sinica, columnName=Professionals Forum, runingTitle=null, highlight=null, articleAbstract=

In 2023, drug discovery develops steadily, with improvement of small molecule drugs discovery keeps pace with biological drugs in this year. The Center for Drug Evaluation and Research of U.S. Food and Drug Administration has totally approved 55 kinds of new drugs which have significantly promotion compared to 37 new drugs approval in 2022, including 38 kinds of new molecular entities, 17 kinds of biological drugs, 5 kinds of gene therapeutics and 2 cell therapeutics. The proportion of first-in-class drugs increased steadily, with 13 small molecule first-in-class drugs and 7 biological first-in-class drugs approved this year, mostly in the fields of cancer and rare diseases. Among them, a plurality of first-initiated small molecule drugs exhibits breakthrough significance, such as the first neurokinin 3 (NK3) receptor antagonist fezolinetant, the first retinoic acid receptor (RIG-I) agonist palovarotene, the first protein kinase B (AKT) inhibitor capivasertib, the first complement factor B inhibitor iptacopan, etc. The pioneering drug has huge academic and commercial value, and has become the target of the academic and industrial circles. However, first-in-class drugs not only need new targets, new mechanisms and new molecules, but also need to comprehensively verify the causality between new targets and diseases, study the correlation between new mechanisms and drug efficacy, and explore the balance between new molecules and drug-manufacturing properties. This article analyzed the research background, development process and therapeutic application of three first-initiated small molecule drugs in this year, expecting to provide more research ideas and methods for more first-in-class drugs.

, correspAuthors=Qi-dong YOU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Lei WANG, Qi-dong YOU), CN=ArticleExt(id=1201124489024205400, articleId=1201124479209533493, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=2023年首创性小分子药物研究实例浅析, columnId=1190335349206389552, journalTitle=药学学报, columnName=专家论坛, runingTitle=null, highlight=null, articleAbstract=

2023年是药物研发稳中求进的一年, 小分子药物与生物药物的研发增长齐头并进。美国FDA药物评价和研究中心(CDER) 在过去一年里共计批准了55款新药, 相比2022年的37款新药获批数量提升明显, 其中包括38款新分子实体、17款生物药物、5款基因疗法和2款细胞疗法。首创性(first-in-class) 药物占比稳步增加, 本年度获批13款小分子首创药物和7款生物首创药物, 多数集中于肿瘤和罕见病领域。其中, 多个首创性小分子药物具有突破性意义, 例如首个神经激肽3 (NK3) 受体拮抗剂非唑奈坦(fezolinetant)、首个视黄酸受体(RIG-I) 激动剂帕拉罗汀(palovarotene)、首个蛋白激酶B (AKT) 抑制剂卡匹色替(capivasertib)、首个补体因子B抑制剂伊普可泮(iptacopan) 等。首创性药物具有巨大的学术价值和商业价值, 已成为当前学术界和工业界争相追寻的目标。然而, 首创性药物不仅需要新靶标、新机制和新分子, 更需要全面验证新靶标与疾病的因果性, 研究新机制与药效之间的关联性, 探索新分子与成药性之间的平衡关系, 研发风险极大。本文通过浅析本年度3个首创性小分子药物的研发背景、研发过程和治疗应用, 以期为更多的首创性药物提供研究思路与方法。

, correspAuthors=尤启冬, authorNote=null, correspAuthorsNote=
*尤启冬, Tel: 86-25-83271351, E-mail:
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DrugINN name (Brand name)SponsorStructureTargetIndicationTypeApproved time
Bexagliflozin (Brenzavvy)TheracosBioSGLT2 inhibitorType 2 diabetesMe-too1-20
Pirtobrutinib (Jaypirca)Eli LillyBTK inhibitorMantle cell lymphomaMe-better1-27
Elacestrant (Orserdu)StemlineER antagonistER+/HER2-ESR1mut mBCMe-better1-27
Daprodustat (Jesduvroq)GSKHIF-PH1-3 inhibitorAnemia due to CKDFirst-in-class2-1
Sparsentan (Filspari)TravereETARAT1R antagonistProteinuria in lgANFirst-in-class2-17
Omaveloxolone (Skyclarys)ReataNrf2 activationFriedrich's ataxiaFirst-in-class2-28
Zavegepant (Zavzpret)PfizerCGRP receptor antagonistMigraineMe-better3-9
Trofinetide (Daybue)AcadiaIGF-1 analogueRett syndromeFirst-in-class/orphan3-10
Rezafungin (Rezzayo)Cidara1, 3-β-D-glucan inhibitorCandidemia & invasive candidiasisOrphan3-22
Leniolisib (Joenja)PharmingPI3Kδ inhibitorActivated PI3Kδ syndromeFirst-in-class/orphan3-24
Fezolinetant (Veozah)AstellasNK3 receptor antagonistVMS due to menopauseFirst-in-class5-12
Perfluorhexyloctane (Miebo)Bausch+Lomb-Dry eye diseasesFirst-in-class5-18
Sulbactam, Durlobactam (Xacduro)InnovivaBeta lactamase inhibitorsAcinetobacter strains-5-23
Nirmatrelvir & Ritonavir (Paxlovid)PfizerSARS-CoV-2 Mpro inhibitor
HIV-1 protease & CYP3A4 inhibitor		COVID-19First-in-class5-25
Flotufolastat F18 (Posluma)Blue Earth DiagnosticsBinds to PSMA & emits β+PET of PSMA+ prostate cancer lesionsMe-too5-25
Sotagliflozin (Inpefa)Lexicon PharmaSGLT1/2 inhibitorHeart failureMe-better5-26
Ritlecitinib (Litfulo)PfizerJAK3/TEC kinase inhibitorSever alopecia areataMe-too6-23
Quizartinib (Vanflyta)Daiichi SankyoFLT3 inhibitorFLT3 ITD+ AMLOrphan7-20
Lotilaner (Xdemvy)TarsusGABA-Cl-channel inhibitorDemodex blephartitisFirst-in-class7-25
Zuranolone (Zurzuvae)SagePAM of GABAA receptorPostpartun depressionMe-better8-4
Palovarotene (Sohonos)IpsenRetinoic acid receptor γ agonistFibrodysplasia ossificansFirst-in-class/orphan8-16
Momelotinib (Ojjaara)GSKJAK1/JAK2/ACVR1 inhibitorAdults with anaemiaOrphan9-15
Gepirone (Exxua)Fabre-Kramer5HT1a receptor agonistMajor depressive disorderMe-too9-22
Etrasimod (Velsipity)PfizerS1P receptor modulatorUlcerative colitisMe-better10-12
Vamorolone (Agamree)SantheraGlucocorticoid receptor agonistDuchenne muscular dystrophyOrphan10-26
Fruquintinib (Fruzaqla)HUTCHMEDVEGFR-1/2/3 inhibitorRefractory, metastatic colorectal cancerMe-too11-8
Repotrectinib (Augtyro)BMSROS1/NTRK inhibitornon-small cell lung cancer (NSCLC) in adults-11-15
Capivasertib (Truqaq)AstraZenecaAKT1/2/3 inhibitorHR+, Her2-locally advanced or mBC with PIK3CA/AKT1/PTEN alterationsFirst-in-class11-16
Nirogacestat (Ogsiveo)SpringWorksGamma secretase inhibitorDesmoid tumorsFirst-in-class/orphan11-27
Iptacopan (Fabhalta)NovartisFactor B inhibitorParoxysmal noctural hemoglobinuriaFirst-in-class/orphan12-5
), ArticleFig(id=1201124493369504634, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124479209533493, language=CN, label=Table 1, caption=

Small molecule drugs approved by FDA in 2023. ACVR1: Recombinant activin A receptor type Ⅰ; AKT1/2/3: Protein kinase B 1/2/3; BTK: Bruton's tyrosine kinase; CGRP: Calcitonin gene-related peptide; CYP: Cytochrome P450 proteins; ER: Estrogen receptor; ETARAT1R: Endothelin (type) a receptor angiotensin (type) 1 receptor; FLT3: FMS-like tyrosine kinease 3; GABA: Gamma (γ)-aminobutyric acid; HIF-PH1-3: Hypoxia inducible factor prolyl hydroxylase1-3; HIV-1: Human immunodeficiency virus; JAK1/2/3: Janus kinases 1/2/3; Mpro: 3C-like protease; NK3: Neurokinin 3; Nrf2: Nuclear factor erythroid-2-related factor 2; PAM of GABAA: Positive allosteric modulators of gamma-aminobutyric acid type A; PI3K-δ: Phosphatidyqinositol-3 kinase δ; PSMA: Prostate-specific membrane antigen; S1P: Sphingosine-1-phosphate; SGLT1/2: Sodium glucose linked transporter 1/2; TEC: Tyrosine kinase expressed in hepatocellular carcinoma; VEGFR: Vascular endothelial growth factor receptor

, figureFileSmall=null, figureFileBig=null, tableContent=
DrugINN name (Brand name)SponsorStructureTargetIndicationTypeApproved time
Bexagliflozin (Brenzavvy)TheracosBioSGLT2 inhibitorType 2 diabetesMe-too1-20
Pirtobrutinib (Jaypirca)Eli LillyBTK inhibitorMantle cell lymphomaMe-better1-27
Elacestrant (Orserdu)StemlineER antagonistER+/HER2-ESR1mut mBCMe-better1-27
Daprodustat (Jesduvroq)GSKHIF-PH1-3 inhibitorAnemia due to CKDFirst-in-class2-1
Sparsentan (Filspari)TravereETARAT1R antagonistProteinuria in lgANFirst-in-class2-17
Omaveloxolone (Skyclarys)ReataNrf2 activationFriedrich's ataxiaFirst-in-class2-28
Zavegepant (Zavzpret)PfizerCGRP receptor antagonistMigraineMe-better3-9
Trofinetide (Daybue)AcadiaIGF-1 analogueRett syndromeFirst-in-class/orphan3-10
Rezafungin (Rezzayo)Cidara1, 3-β-D-glucan inhibitorCandidemia & invasive candidiasisOrphan3-22
Leniolisib (Joenja)PharmingPI3Kδ inhibitorActivated PI3Kδ syndromeFirst-in-class/orphan3-24
Fezolinetant (Veozah)AstellasNK3 receptor antagonistVMS due to menopauseFirst-in-class5-12
Perfluorhexyloctane (Miebo)Bausch+Lomb-Dry eye diseasesFirst-in-class5-18
Sulbactam, Durlobactam (Xacduro)InnovivaBeta lactamase inhibitorsAcinetobacter strains-5-23
Nirmatrelvir & Ritonavir (Paxlovid)PfizerSARS-CoV-2 Mpro inhibitor
HIV-1 protease & CYP3A4 inhibitor		COVID-19First-in-class5-25
Flotufolastat F18 (Posluma)Blue Earth DiagnosticsBinds to PSMA & emits β+PET of PSMA+ prostate cancer lesionsMe-too5-25
Sotagliflozin (Inpefa)Lexicon PharmaSGLT1/2 inhibitorHeart failureMe-better5-26
Ritlecitinib (Litfulo)PfizerJAK3/TEC kinase inhibitorSever alopecia areataMe-too6-23
Quizartinib (Vanflyta)Daiichi SankyoFLT3 inhibitorFLT3 ITD+ AMLOrphan7-20
Lotilaner (Xdemvy)TarsusGABA-Cl-channel inhibitorDemodex blephartitisFirst-in-class7-25
Zuranolone (Zurzuvae)SagePAM of GABAA receptorPostpartun depressionMe-better8-4
Palovarotene (Sohonos)IpsenRetinoic acid receptor γ agonistFibrodysplasia ossificansFirst-in-class/orphan8-16
Momelotinib (Ojjaara)GSKJAK1/JAK2/ACVR1 inhibitorAdults with anaemiaOrphan9-15
Gepirone (Exxua)Fabre-Kramer5HT1a receptor agonistMajor depressive disorderMe-too9-22
Etrasimod (Velsipity)PfizerS1P receptor modulatorUlcerative colitisMe-better10-12
Vamorolone (Agamree)SantheraGlucocorticoid receptor agonistDuchenne muscular dystrophyOrphan10-26
Fruquintinib (Fruzaqla)HUTCHMEDVEGFR-1/2/3 inhibitorRefractory, metastatic colorectal cancerMe-too11-8
Repotrectinib (Augtyro)BMSROS1/NTRK inhibitornon-small cell lung cancer (NSCLC) in adults-11-15
Capivasertib (Truqaq)AstraZenecaAKT1/2/3 inhibitorHR+, Her2-locally advanced or mBC with PIK3CA/AKT1/PTEN alterationsFirst-in-class11-16
Nirogacestat (Ogsiveo)SpringWorksGamma secretase inhibitorDesmoid tumorsFirst-in-class/orphan11-27
Iptacopan (Fabhalta)NovartisFactor B inhibitorParoxysmal noctural hemoglobinuriaFirst-in-class/orphan12-5
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2023年首创性小分子药物研究实例浅析
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王磊 1, 2 , 尤启冬 1, 2, *
药学学报 | 专家论坛 2024,59(3): 493-502
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药学学报 | 专家论坛 2024, 59(3): 493-502
2023年首创性小分子药物研究实例浅析
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王磊1, 2, 尤启冬1, 2, *
作者信息
  • 1.中国药科大学, 江苏省药物分子设计与成药性优化重点实验室, 江苏 南京 210009
  • 2.中国药科大学药学院, 药物化学系, 江苏 南京 210009

通讯作者:

*尤启冬, Tel: 86-25-83271351, E-mail:
First-in-class small molecule drugs in 2023
Lei WANG1, 2, Qi-dong YOU1, 2, *
Affiliations
  • 1. Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
出版时间: 2024-03-12 doi: 10.16438/j.0513-4870.2024-0082
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2023年是药物研发稳中求进的一年, 小分子药物与生物药物的研发增长齐头并进。美国FDA药物评价和研究中心(CDER) 在过去一年里共计批准了55款新药, 相比2022年的37款新药获批数量提升明显, 其中包括38款新分子实体、17款生物药物、5款基因疗法和2款细胞疗法。首创性(first-in-class) 药物占比稳步增加, 本年度获批13款小分子首创药物和7款生物首创药物, 多数集中于肿瘤和罕见病领域。其中, 多个首创性小分子药物具有突破性意义, 例如首个神经激肽3 (NK3) 受体拮抗剂非唑奈坦(fezolinetant)、首个视黄酸受体(RIG-I) 激动剂帕拉罗汀(palovarotene)、首个蛋白激酶B (AKT) 抑制剂卡匹色替(capivasertib)、首个补体因子B抑制剂伊普可泮(iptacopan) 等。首创性药物具有巨大的学术价值和商业价值, 已成为当前学术界和工业界争相追寻的目标。然而, 首创性药物不仅需要新靶标、新机制和新分子, 更需要全面验证新靶标与疾病的因果性, 研究新机制与药效之间的关联性, 探索新分子与成药性之间的平衡关系, 研发风险极大。本文通过浅析本年度3个首创性小分子药物的研发背景、研发过程和治疗应用, 以期为更多的首创性药物提供研究思路与方法。

首创性药物  /  新药创制  /  小分子药物

In 2023, drug discovery develops steadily, with improvement of small molecule drugs discovery keeps pace with biological drugs in this year. The Center for Drug Evaluation and Research of U.S. Food and Drug Administration has totally approved 55 kinds of new drugs which have significantly promotion compared to 37 new drugs approval in 2022, including 38 kinds of new molecular entities, 17 kinds of biological drugs, 5 kinds of gene therapeutics and 2 cell therapeutics. The proportion of first-in-class drugs increased steadily, with 13 small molecule first-in-class drugs and 7 biological first-in-class drugs approved this year, mostly in the fields of cancer and rare diseases. Among them, a plurality of first-initiated small molecule drugs exhibits breakthrough significance, such as the first neurokinin 3 (NK3) receptor antagonist fezolinetant, the first retinoic acid receptor (RIG-I) agonist palovarotene, the first protein kinase B (AKT) inhibitor capivasertib, the first complement factor B inhibitor iptacopan, etc. The pioneering drug has huge academic and commercial value, and has become the target of the academic and industrial circles. However, first-in-class drugs not only need new targets, new mechanisms and new molecules, but also need to comprehensively verify the causality between new targets and diseases, study the correlation between new mechanisms and drug efficacy, and explore the balance between new molecules and drug-manufacturing properties. This article analyzed the research background, development process and therapeutic application of three first-initiated small molecule drugs in this year, expecting to provide more research ideas and methods for more first-in-class drugs.

first-in-class drug  /  drug discovery  /  small molecule drug
王磊, 尤启冬. 2023年首创性小分子药物研究实例浅析. 药学学报, 2024 , 59 (3) : 493 -502 . DOI: 10.16438/j.0513-4870.2024-0082
Lei WANG, Qi-dong YOU. First-in-class small molecule drugs in 2023[J]. Acta Pharmaceutica Sinica, 2024 , 59 (3) : 493 -502 . DOI: 10.16438/j.0513-4870.2024-0082
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新药创制对于人民健康、民族复兴和创新型国家的建设至关重要[1]。对于新药创制而言, 大体可分为首创性(first-in-class) 药物和跟随性(me-too, me-better) 药物, 二者均具有重要意义(关于首创性药物与跟随性药物的概述, 笔者在前文[2-6]中已有所阐述)。20世纪80年代前后被视为跟随性药物研发的黄金时代, 有机化学与结构生物学的蓬勃发展加速了跟随性药物的成功。由于当时研究人员对药物有限的认知水平, 导致获批上市的首创性药物常常也存在着许多缺陷, 给跟随性药物的研发留下了巨大空间。随着新药创制技术的不断进步, 很多疾病已经有了日趋合理的治疗方案, 甚至有很多同类型的药物可供选择。尽管如此, 目前仍有很多尚未攻克的、对人民生命健康造成巨大威胁的疾病没有针对性的治疗方案。对于很多亟待解决的难题, 首创性药物的研发受到越来越多的关注, 而跟随性药物的空间变小, 风险滞后。回顾历史不难发现, 具有影响性的药物多为首创性药物, 例如意外发现的磺胺和青霉素, 是抗菌药物划时代的产物; 首个经理性药物设计得到H2受体拮抗剂西咪替丁, 成为基于内源性底物设计药物分子的重要基石; 首个质子泵抑制剂奥美拉唑的问世成功替代了“替丁”药物, 成为抗胃溃疡药物的首选; 首个降胆固醇药物洛伐他汀的发现开启了HMG-CoA抑制剂设计的浪潮; 首个靶向蛋白激酶的药物伊马替尼更是成为现在所有激酶类抗肿瘤药物的“引路人”。随着基础研究的不断深入, 原创靶标、首创药物分子的研究已成为学术界和工业界争相追求的对象。首创药物分子受到越来越多的关注, 同样也进一步提高了跟随性药物的研发门槛, 很多没有任何改善或研究特色的跟随性药物不再受到欢迎。
2023年, 美国FDA药物评价和研究中心(Center for Drug Evaluation and Research, CDER) 共批准上市新药55款, 包括38款新分子实体和17款生物药物, 包括了5款细胞疗法和2款基因疗法。相比2022年的37款新药获批, 今年的新药总数大幅度上升。近10年获批新药数量均值达到46款。从获批新药的适应症分布可以发现本年度新药获批与2022年度的适应症类型较为相似, 其中抗肿瘤药物共计获批13款, 占到24%; 神经系统疾病药物紧随其后, 获批9款, 占比16%; 抗感染与血液病相关药物各获批5款, 分别占比9%。从获批新药的评审特点上可以发现, 2023年获批的新药分子中有25款新药获得了“优先评审”资格, 9款新药获得加速审批上市资格。本年度获批新药分子中孤儿药仍有较高的占比(51%), 获批28款, 连续多年占据了获批总数的半数以上, 另外还有9款药物获得了突破性疗法认定。2023年共有20款首创性药物获批, 占比36%, 是上市药物的主力军。有35款药物(66%) 是在美国首次获批上市(www.fda.gov)。
本年度20个首创性药物中包括13个首创性小分子药物(表 1)。多款小分子药物具有突破性意义, 例如1月27日获批的BTK非共价抑制剂匹妥布替尼(pirtobrutinib), 是目前唯一可逆的BTK抑制剂, 用于治疗复发或难治性套细胞淋巴瘤(MCL); 2月1日获批的缺氧诱导因子-脯氨酰羟化酶(HIF-PHD) 抑制剂达普司他(daprodustat), 是FDA批准的首款口服治疗慢性肾病引起的贫血药物; 2月28日获批的Nrf2激动剂奥马索龙(omaveloxolone), 是首个也是目前唯一用于治疗弗里德赖希共济失调症(FA) 的小分子药物; 3月10日获批的IGF-1 (胰岛素样生长因子1) 的氨基末端三肽类似物(曲非奈肽, trofinetide), 是首款用于治疗Rett综合征的药物; 3月24日获批的活化磷酸肌醇3-激酶-δ (PI3K-δ) 抑制剂是首款针对PI3K-δ过度活化综合征(APDS) 的药物(莱尼利塞, leniolisib); 5月18日获批的半氟化烷烃类药物(perfluorohexyloctane) 是首款治疗干眼症的处方滴眼液; 7月20日获批的第二代FLT3激酶小分子抑制剂, 是首款专门用于治疗FLT3-ITD阳性的急性髓系白血病(AML) 药物; 7月25日获批的高选择性γ-氨基丁酸(GABA) 门控氯离子通道抑制剂(洛替拉纳, lotilaner), 是首个用于治疗蠕形螨睑缘炎的根治疗法; 8月16日获批的视黄酸受体激动剂(帕拉罗汀, palovarotene) 是首个治疗进行性骨化性纤维发育不良, 俗称“石头人症”的药物; 9月22日获批的5HT1A受体的选择性激动剂(吉哌隆, gepirone) 是首个可口服使用治疗重度抑郁症的药物; 11月16日获批的丝氨酸/苏氨酸激酶AKT抑制剂(卡匹色替, capivasertib) 是首个AKT的ATP竞争型抑制剂, 与氟维司群联合用于治疗乳腺癌。以上药物均通过全新的作用机制实现了对多种难治疾病的治疗目的, 在多种疾病上实现了“首次”的突破, 为无药可用的患者提供了希望。很多首创性药物分子的研究过程, 也为后续的药物研发提供了广阔的思路与研究借鉴。
本文选取3个具有代表性的首创性小分子药物, 通过药物化学视角阐述其研发背景、药物设计思路及治疗学应用, 以期为更多的首创性小分子药物设计提供思路与帮助。
1 非唑奈坦(fezolinetant)——全球首个靶向神经激肽3 (NK3) 受体的小分子拮抗剂用于治疗更年期引起的中度至重度血管舒缩症状
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1.1 研发背景
血管收缩症状(VMS) 是一种女性常见的更年期相关症状, 据统计约有超过50%的女性患者受到此类疾病的困扰, 症状常发作于最后月经期之前, 持续时间可达约7年。血管收缩的症状会造成女性身体产生严重不适, 进而影响睡眠并导致疲乏和情绪波动, 对日常生活造成较大困扰。超过三分之一的女性会在十多年的时间里感受到中度至重度的潮热症状(一种主观感觉, 包括大量出汗、皮肤血管舒张以及随后由于快速而过度的散热反应导致的核心体温下降等)。目前, 对于VMS的治疗仍采用传统的激素替代疗法, 常见使用的是雌激素或雌激素和孕激素的联用。激素疗法虽在短时间内有效且安全, 但长期使用会增加潜在的静脉血栓栓塞风险, 且不宜用于心脑血管疾病和恶性肿瘤风险较高的患者。其他治疗方案应用有限, 主要包括选择性5-羟色胺再摄取抑制剂(SSRI)、选择性5-羟色胺和去甲肾上腺素双重再摄取抑制剂等。2013年7月, FDA批准了抗抑郁药物帕罗西汀作为老药新用上市, 用于治疗中重度更年期妇女血管舒缩症状, 它也成为首款经FDA批准治疗更年期妇女VMS的非激素药物。
随着对神经调控机制的深入研究, 诱发热潮的病因越发清晰, 出现了部分潜在的治疗靶点(图 1A)。绝经期的最典型特征是由于卵巢功能逐渐丧失所导致的雌激素水平下降, 这一现象会使得促性腺激素释放激素(GnRH) 以及黄体生成激素(LH) 和促卵泡激素(FSH) 浓度增加。其中, GnRH的分泌主要由kisspeptin调节, kisspeptin与神经激肽B (NKB) 和强啡肽(Dyn), 形成KNDy神经元。在绝经期雌激素缺乏的状态下, 雌激素负调节因子kisspeptin、NKB、Dyn及其受体的表达显著增加。其中, NKB主要通过神经激肽3受体(NK3R) 传递信号, 是绝经期潮热发生的关键因素。随后的研究表明, 育龄女性来自循环雌激素的负反馈有助于调节KNDy神经元的激活, 不易产生潮热症状。而绝经后的女性kisspeptin和NKB的表达增加, 导致体内散热效应的异常激活, 最终导致潮热症状(图 1B)。因此, 针对NKB/NK3R通路设计药物分子有望通过全新的作用机制治疗VMS, 引起了全球研究人员的广泛关注。
1.2 研发过程
NK3R是中枢神经系统中神经肽Y (NPY) 受体家族的重要成员, 该受体主要分布于大脑皮层、下丘脑和海马体等区域。NK3R具有重要生理功能, 负责调控多种神经活动, 包括食欲、睡眠、注意力等。正常生理状态下, 体温调节中枢由NK3的正向调控和雌激素的负向调控维持于平衡状态, 但这一平衡在绝经期因雌激素减少而被破坏, 最终导致VMS。NK3R是一种A类G蛋白偶联受体(GPCR), 是下丘脑-垂体-性腺轴必需的速激肽受体, NK3R的功能是通过与其高亲和力配体神经激肽B (NKB) 结合而起作用, 内源性肽激动剂NKB优先激活NK3R。NK3R在调节强直性搏动性GnRH释放方面发挥重要作用, 可潜在地受益于降低GnRH搏动, 从而降低血浆LH水平, 并相应减弱循环雄激素和雌激素水平[7]。
非唑奈坦是Astellas公司通过高通量筛选后经系统性结构优化而得。研究人员首先认识到早期报道的非肽NK3R拮抗剂(osanetant与talnetant) 的作用机制并不准确, 为了避免陷入肽类调控剂带来的“结构优化陷阱”, 研究人员首先优化了活性测试方法以期通过高通量筛选获得可靠的分子结构。经过第一轮的筛选验证与优化, 最终确定了以4-嘧啶基-2-吡啶基-乙腈结构为特征的苗头化合物(1), 其体外活性已达到纳摩尔级水平(IC50 = 76 nmol·L-1)。但随后的测试发现了化合物(1) 的若干缺点, 包括溶解度差、微粒体稳定性低和脱靶带来的潜在安全性问题, 不得不让研究人员最终放弃了化合物(1) 的进一步优化, 转而通过积累的SAR经验寻找避开化合物(1) 结构的新骨架类型。通过高通量筛选和经验分析, 研究人员确证了新型的N-酰基-三唑并哌嗪类化合物(2), 其保持了和化合物(1) 超过70%的相似度。尽管化合物(2) 的体外活性下降至微摩尔级别(IC50 = 4.5 μmol·L-1), 但其表现出较好的CYP选择性、较好的口服利用度以及较少的脱靶效应和较好的PK-ADME等性质, 值得进一步的活性优化。在4-氟苯基的优化过程中, 研究人员发现供电子基团的引入以及芳杂环的取代均会导致化合物活性的降低。在哌嗪环的优化中, 研究人员发现了神奇甲基效应(magical methyl effect), 即通过向化合物(2) 的哌嗪环上引入甲基可以使其生物活性提升10倍, 同时不会导致配体亲脂性效率(LLE) 的降低以及溶解度的下降。在吡啶环的优化过程中, 研究人员使用同系物2-甲基噻唑环的替换策略, 辅以X射线晶体结构研究, 得到了活性提升(IC50 = 12.59 nmol·L-1) 且可口服使用的先导物(3)[8, 9]。随后, 研究人员将目标锁定在化合物的成药性优化。在将2-甲基噻唑环替换为1, 2, 4-噻二唑环后, 发现此结构片段对活性必不可少, 故将其保留。与此同时, 研究团队将中间体的4-(噻吩-2-基) 苯基改回了早期苗头化合物的4-氟苯环, 导致亲脂性的降低(ΔlogD7.4 = -1.5), 但同时带来的LLE的提升以及安全性的提升, 这被认为更加重要[10]。最终获得的化合物(4) 即为非唑奈坦(图 1C), 其保持了纳摩尔级活性, 具有更小的分子量和更好的生物利用度, 最终被选为候选分子进入临床研究, 并成功上市。
1.3 治疗应用
非唑奈坦的成功获批主要归功于关键Ⅲ期SKYLIGHT 1 (NCT04003155) 和SKYLIGHT 2 (NCT04003142) 研究的疗效和安全性数据, 以及SKYLIGHT 4安全性扩展研究(NCT04003389)。临床研究在1 022名40~65岁的女性患者(有中度至重度血管舒缩症状) 中开展, 采用每日口服一次的方案(30和45 mg) 评价疗效和安全性。两项试验的结果均表明, 在第4周和第12周时, 与安慰剂相比, 使用45 mg非唑奈坦后VMS的出现频率降低表现出统计学和临床意义(≥24 h内出现2次潮热)。在安全性方面, 非唑奈坦的最常见不良反应是腹痛、腹泻、失眠、背痛、潮热和肝转氨酶升高。非唑奈坦是首创性的NK3R小分子受体拮抗剂, 证明了通过阻断NKB与KNDy神经元的结合可以有效调节下丘脑中的体温调节中心神经元活动, 是目前本领域获批的唯一的非激素类疗法, 为中度至重度更年期潮热女性提供了一种额外的安全有效的治疗选择。
2 卡匹色替(capivasertib)——全球首个靶向蛋白激酶AKT的小分子抑制剂用于治疗乳腺癌
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2.1 研发背景
乳腺癌是目前全球范围内癌症相关死亡的最主要原因之一。2020年, 全球超过200多万名患者被诊断为乳腺癌, 有近685 000名患者死亡, 其中HR+ (雌激素或孕激素受体表达) 与HER2- (人表皮生长因子受体-2) 乳腺癌是最常见的亚型, 所占比例超过70%。这部分患者的标准疗法为内分泌治疗药物, 其中CDK4/6抑制剂与芳香化酶抑制剂是其标准的一线治疗方案。目前, 已发现大量患者对上述用药方案产生耐药性, 亟需新机制的药物分子。大量研究已经表明, PI3K/AKT/mTOR通路是多种恶性肿瘤发生、发展与转移的关键信号通路之一。其中, PIK3CA、AKT1和PTEN基因的异常突变占总体HR+/HER2-乳腺癌患者的比例高达50%。因此, 为了进一步解决HR+/HER2-乳腺癌内分泌治疗耐药的临床问题, 针对PI3K/AKT/mTOR通路开发药物分子已成为公认的研究热点(图 2A、B)[11, 12]。
在AKT抑制剂获批上市之前, 已有PI3K的抑制剂阿吡利塞(alpelisib) 和mTOR抑制剂依维莫司(everolimus) 成功上市, 用于乳腺癌治疗。然而, 作为PI3K/AKT/mTOR通路的关键中心环节, AKT的结构、调控机制已发现30余年, 但其可药性验证却迟迟未能实现。回顾AKT小分子抑制剂的研发历程, 最早进入临床试验的是葛兰素史克的小分子抑制剂GSK-690693, 但在临床I期试验中表现出安全性问题, 早早终止了进一步的研发; 随后, 被寄予厚望的礼来公司研发的AKT/RSK的双靶点抑制剂LY2780301因有效性不佳而折戟于临床Ⅱ期; 接下来, 同样因为临床有效性不足而失败于临床Ⅱ期的还有拜耳的小分子抑制剂BAY1125976以及默沙东的小分子抑制剂MK-2206; 更加不幸的是, 临床进展较快的罗氏小分子抑制剂帕他色替(ipatasertib) 于2020年相继中止了两项Ⅲ期乳腺癌临床试验。这些研究早期的失败案例都给AKT药物的研发蒙上了层层阴霾, 部分原因归结为AKT1/2/3的3种亚型序列高度同源性(高达80%以上), 导致小分子难以实现选择性调控, 此外早期的AKT抑制剂还存在生物利用度低、严重的不良反应、不足的治疗效果, 以及狭窄的治疗窗口等诸多问题。
2.2 研发过程
在认识到AKT的重要功能后, 其抑制剂的开发很快就成为世界范围内的研究热点。目前已有超过20项AKT抑制剂处于临床试验阶段, 包括针对变构位点的AKT抑制剂MK-2206 (5), 其对AKT1具有一定的选择性(AKT1/2/3 IC50 = 8.0/12.0/65.0 nmol·L-1), 以及AKT的ATP竞争型抑制剂GDC-0068 (6), 其对AKT的3种亚型均有较好的抑制活性(AKT1/2/3 IC50 = 5.0/18.0/8.0 nmol·L-1)。基于化合物(5) 和(6) 的结构特点, 阿斯利康公司的研究人员参考复合物晶体结构(图 2C) 逐步发现了优势骨架结构(吡咯并嘧啶环)。在此结构基础上, 由哌啶对位引出的氨基、羰基等官能团可作为氢键供体与Glu234和Glu278形成氢键相互作用, 其余的疏水作用由ATP结合位点下方的疏水腔穴提供。基于以上思路, 经构效关系研究确定了化合物的基本结合模式, 其代表性结构为化合物(7)。尽管化合物(7) 已经具有纳摩尔级的体外AKT酶活抑制活性(AKT1/2/3 IC50 = 4.0/22.0/15.0 nmol·L-1), 但其对hERG仍有较强的抑制活性, 存在潜在的安全性风险(hERG IC50 = 26.96 μmol·L-1)。接下来, 将4-F苯基替换为4-Cl苯基, 并在其α位引入羟基侧链后得到化合物(8), 其在活性保持的同时hERG脱靶毒性已几乎完全消除(hERG IC50 > 100 μmol·L-1)。最后, 将氨基连接部分替换为酰胺, 并分离出活性更高的S-优映体(9) 即为卡匹色替(AZD-5363) (图 2D)。该化合物显示出强效的泛AKT抑制活性(AKT1/2/3 IC50 = 3~8 nmol·L-1)、抗细胞增殖活性(IC50 = 89 nmol·L-1)、较高的hERG安全性(IC50 > 100 μmol·L-1) 和优良的溶解度。后续研究也验证了R-对映异构的活性大幅降低, 证明了此类结构的手性偏好[13-15]。
2.3 治疗应用
卡匹色替是靶向AKT ATP位点的首创性小分子药物, 对AKT1/2/3均有较高的抑制活性, 可作为口服药物以4天用药、3天停药的给药方案使用。对于PI3K/AKT通路异常突变的乳腺癌患者, 卡匹色替联合氟维司群可将疾病进展或死亡风险降低50% (相比于氟维司群单独用药)。2023年12月5日, 乳腺癌NCCN更新了治疗指南, 补充了卡匹色替联合氟维司群作为PI3K/AKT1/PTEN突变HR+/HER2-晚期乳腺癌患者的二线及以上治疗。虽然卡匹色替作为首创性的AKT小分子抑制剂具有里程碑式的重要意义, 但从适应症方面来看, 卡匹色替还有明显的缺陷。卡匹色替仅被获批用于治疗伴有一种或多种生物标志物改变(如PIK3CA、AKT1或PTEN), 且对芳香化酶抑制剂耐药的HR+/HER2-晚期乳腺癌患者, 患者群体总量有限。考虑到这一问题, 目前包括卡匹色替在内的多个AKT抑制剂临床中也在逐步探索其他肿瘤适应症。卡匹色替的成功获批, 初步验证了AKT作为药物靶标的可药性, 为更多的AKT抑制剂研究提供了研究范例。
3 伊普可泮(iptacopan)——全球首个可逆性补体因子B (FB) 小分子抑制剂用于治疗成人阵发性睡眠性血红蛋白尿
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3.1 研发背景
阵发性夜间血红蛋白尿症(PNH) 是一种罕见的慢性血液疾病, 主要由补体功能激活而介导, 临床主要表现为不同程度的血管内溶血、阵发性血红蛋白尿、骨髓造血功能衰竭和静脉血栓形成等。PNH患者的骨髓中常见造血干细胞的多种突变, 主要包括PIG-A基因突变, 并导致血细胞表面上重要的补体调节蛋白CD55和CD59缺失, 使得补体系统更易被激活。PNH的全球发病率约为1~2人/百万人, 亚洲地区发病率相对较高。PNH尚无有效治愈手段, 设法抑制溶血的发生是临床治疗的主要手段。目前, 抗补体C5疗法是国际公认的PNH治疗标准, 但效果有限, 已获批上市的补体C5抑制剂药物仅有Soliris (依库珠单抗eculizumab) 和Ultomiris (瑞利珠单抗ravulizumab)。大部分患者使用此疗法后仍有贫血、疲乏和输血依赖等症状, 生活质量受到严重影响, 亟需新机制的药物分子[16]。
补体系统是机体固有免疫的重要组成部分, 由经典通路、替代通路和凝集素通路3种途径之一激活, 产生后续的蛋白水解功能, 形成膜攻击复合物(MAC) 以增强免疫反应。C1处于经典通路的上游, C3属于3条通路的汇集点, 而C5则位于通路末端(图 3A)。在正常情况下, CD59能阻止补体反应的最后一步, 防止血管内溶血。倘若患者红细胞缺乏, 将引起CD59功能失效并导致血管内溶血。靶向末端补体C5能阻止MAC复合物的形成, 阻断血管内溶血。可逆性补体因子B (CFB) 是一种丝氨酸蛋白酶, 可作为补体系统替代途径的关键因子, 亦是调节补体旁路途径级联反应的必需蛋白。在调控过程中, CFB被补体因子D分解为两个亚基Ba和Bb, 其中Bb与C3b形成替代途径的C3转化酶C3bBb, 随后形成C5转化酶(C3bBbC3b) 并最终形成膜攻击复合物诱发免疫反应。因此, 靶向CFB可有效抑制MAC的生成, 进而减弱免疫反应, 控制PNH的发生与发展[17]。
3.2 研发过程
在2010年, 为了得到可靠的先导物, 研究人员综合运用了多种分子发现方法, 主要包括①基于MAC形成功能开展高通量筛选(诺华公司的化合物库, 约110万个化合物); ②基于核磁共振和晶体复合物的片段结构筛选(FBDD)。最终, FBDD方法以0.6%的命中率得到了具有氨基咪唑啉骨架的化合物(10)。化合物(10) 具有微摩尔级别的体外活性(IC50 = 6.6 μmol·L-1, Kd = 10 μmol·L-1) 并成功获得与CFB的共晶复合物结构(图 3B)。晶体结构显示, 咪唑啉环处在由Glu97、Tyr99、Tyr172F、Pro172D组成的S3腔穴中, 与Gly216的骨架羰基形成氢键。后续的优化重点围绕对S3腔穴的优势结构而展开, 研究人员尝试了苯并咪唑衍生物与四氢嘧啶等替换咪唑啉, 但都因生物活性的丧失而以失败告终。随后历经3年时间, 大量的SAR研究表明将咪唑啉替换为乙胺、吗啉等基团后均会导致活性丧失, 只有哌啶结构的衍生物保留了微摩尔级别的活性(IC50 = 5.9 μmol·L-1)。在此位置多引入一个羧基得到化合物(11), 其CFB的体外活性提高了近100倍(IC50 = 0.033 μmol·L-1)。共晶复合物表明化合物(11) 的活性提升源自其与Asn220和Asp218形成了额外的氢键相互作用。哌啶环4位引入甲氧基可通过额外的疏水作用力而使得活性部分提高。综合以上关键的构效关系分析, 在2019年最终将优势片段组合后得到化合物(12) (图 3C), 展现出最优的活性(IC50 = 0.001 2 μmol·L-1)。化合物(12) 同时具有较好的安全性指标, 达到了活性、理化性质与安全性的平衡, 因此作为候选药物进入临床并最终成为本领域中FDA首个批准上市的药物。从以上研发历程可以发现, 从先导化合物的发现到候选药物的确定, 需要长时间的探索与大量化合物的积累, 彰显出过程之艰辛[18-20]。
3.3 治疗应用
伊普可泮作为一款特异性CFB抑制剂, 通过作用于C5末端通路上游控制血管内外的溶血, 较好地弥补了抗C5抗体的缺陷, 为PNH患者提供了治疗新选择。CFB抑制剂具有全新的作用机制, 除了治疗PNH外, 伊普可泮也在其他许多补体介导疾病的相关研究中处于关键阶段, 其中包括肾脏疾病C3肾小球病(C3G)、IgA肾病(IgAN)、非典型溶血性尿毒症综合征(aHUS)、膜性肾病(MN)、狼疮性肾炎(LN) 以及免疫性血小板减少性紫癜(ITP) 和冷凝集素病(CAD)。伊普可泮通过全新的作用机制, 作为首创性小分子药物展现出显著的临床优势, 有望打破现有PNH治疗格局, 重新定义治疗标准。由伊普可泮的研发过程可以看出, 具有全新作用机制的药物分子一旦完成可药性验证, 可以大大拓宽一类疾病的治疗选择, 为患者提供更多、更优的治疗选择。依普可泮在CFB靶标上的成功, 也给予该靶标其他在研药物较大的信心。目前在研的CFB靶向药种类较多, 涉及小分子药物、单克隆抗体、ASO疗法、RNAi疗法等。靶向CFB药物的成功, 也将为更多的肾病患者带来新希望。
4 结语与展望
收起
2023年, 我国药品监督管理局(NMPA) 共批准上市了82款新药, 相比去年的49款新药有大幅提高, 为近年来新高。其中包括48款小分子化学药、22款生物药、4款疫苗和8款中药。与FDA获批新药相似的是, 从疾病领域来看, NMPA批准新药中肿瘤领域获批数量最多, 共计24款, 占比高达33%。国产创新药持续发力, 多款药物也实现了“首次”的突破, 例如恒瑞医药研发的磷酸瑞格列汀, 是中国首个自主研发的DPP-4抑制剂; 轩竹(北京) 医药研发的安奈拉唑是中国首个自主研发的质子泵抑制剂等。2023年我国新药获批数量呈明显的上升趋势, 其中国产创新药占主要比例, 进口创新药的空间减少。首创性药物或重磅药物的发现, 不仅可以获得丰厚的利润, 更重要的是对于药物分子认知的突破、药物发现技术的突破、原创靶标理解的突破。在新的一年里, 期待有更多的首创性药物被贴上中国标签, 有更多的新药、好药造福患者。
作者贡献: 王磊负责文章资料收集与撰写; 尤启冬负责文章的选题与修改, 为该文章的主要负责人。
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基金
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  • 国家自然科学基金资助项目(82173741)
  • 国家自然科学基金资助项目(82003582)
  • 国家自然科学基金资助项目(81930100)
文献
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2024年第59卷第3期
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doi: 10.16438/j.0513-4870.2024-0082
  • 接收时间：2024-01-26
  • 首发时间：2025-11-28
  • 出版时间：2024-03-12
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  • 收稿日期：2024-01-26
  • 修回日期：2024-01-31
基金
国家自然科学基金资助项目(82173741)
国家自然科学基金资助项目(82003582)
国家自然科学基金资助项目(81930100)
作者信息
    1.中国药科大学, 江苏省药物分子设计与成药性优化重点实验室, 江苏 南京 210009
    2.中国药科大学药学院, 药物化学系, 江苏 南京 210009

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
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