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Article(id=1210516751104733742, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210516741998907791, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-0602, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1652803200000, receivedDateStr=2022-05-18, revisedDate=1655136000000, revisedDateStr=2022-06-14, acceptedDate=null, acceptedDateStr=null, onlineDate=1766539283776, onlineDateStr=2025-12-24, pubDate=1665504000000, pubDateStr=2022-10-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766539283776, onlineIssueDateStr=2025-12-24, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766539283776, creator=13701087609, updateTime=1766539283776, updator=13701087609, issue=Issue{id=1210516741998907791, tenantId=1146029695717560320, journalId=1189982191388893191, year='2022', volume='57', issue='10', pageStart='1', pageEnd='3258', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766539281606, creator=13701087609, updateTime=1766539576214, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1210517977762500872, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210516741998907791, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1210517977762500873, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1210516741998907791, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=3133, endPage=3145, ext={EN=ArticleExt(id=1210516753386435302, articleId=1210516751104733742, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Research progress of leukotriene B4 receptor antagonists, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Leukotriene B4 (LTB4) is a proinflammatory lipid mediator that is synthesized by a number of inflammatory cells. Binding of LTB4 to its receptor leukotriene B4 receptor 1 (BLT1) can migrate neutrophils and macrophages to inflammatory sites through chemotaxis and up-regulation of adhesion molecules. Many researches have shown that LTB4-BLT1 axis is related to the occurrence of autoimmune disorders and other inflammatory diseases. Receptor antagonists of LTB4 are thus expected to be useful therapeutics for these diseases. In this review, we briefly describe the biological function of LTB4 and summarize the preclinical and clinical developments of LTB4 receptor antagonists.

, correspAuthors=Xian-dao PAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2022 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=Tian-tian ZHAO, Long-ying SHEN, Xian-dao PAN), CN=ArticleExt(id=1210516768829862586, articleId=1210516751104733742, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=白三烯B4受体拮抗剂的研究进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

白三烯B4 (leukotriene B4, LTB4) 是一种促炎调节因子, 多数炎症细胞均可产生。LTB4与其受体BLT1 (leukotriene B4 receptor 1) 结合后可通过趋化作用和黏附分子上调将嗜中性粒细胞和巨噬细胞迁移至炎症部位。大量研究表明LTB4-BLT1轴与自身免疫性疾病及炎症的发生有关。因此, LTB4受体拮抗剂对治疗这类疾病具有重要作用。本文简略描述了LTB4的作用, 综述了目前处于临床或临床前研究的LTB4受体拮抗剂的研究进展。

, correspAuthors=潘显道, authorNote=null, correspAuthorsNote=
*潘显道, Tel: 86-10-63166764, E-mail:
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Pharmaceutical preparations containing synergistic oncolytic combinations for the treatment of cancer: WO, 2001034134 [P]. 2001-05-17., articleTitle=null, refAbstract=null)], funds=[Fund(id=1210516775674966890, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, awardId=2021-1-I2M-028, language=CN, fundingSource=中国医学科学院医学与健康科技创新工程项目(2021-1-I2M-028), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1210516769077326533, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, xref=null, ext=[AuthorCompanyExt(id=1210516769081520837, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, companyId=1210516769077326533, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1210516769089909446, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, companyId=1210516769077326533, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 北京 100050)])], figs=[ArticleFig(id=1210516770956374815, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=Oly47bi6iBjUA1kdbey3Kw==, figureFileBig=JhnTQVOnluMW6oBTgye69A==, tableContent=null), ArticleFig(id=1210516771052843813, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 1, caption= The structure of leukotriene B<sub>4</sub> (LTB<sub>4</sub>) (<strong>1</strong>) , figureFileSmall=Oly47bi6iBjUA1kdbey3Kw==, figureFileBig=JhnTQVOnluMW6oBTgye69A==, tableContent=null), ArticleFig(id=1210516771287724841, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=KfI0Eu3m1+XxH0GozGq6mQ==, figureFileBig=ry6JLDk7gU4/PajeR+FHhA==, tableContent=null), ArticleFig(id=1210516771384193837, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 2, caption= Overview of the arachidonic acid (AA) metabolism pathways , figureFileSmall=KfI0Eu3m1+XxH0GozGq6mQ==, figureFileBig=ry6JLDk7gU4/PajeR+FHhA==, tableContent=null), ArticleFig(id=1210516772592153392, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=LKiuI1aL6EQpbFF0up8HPw==, figureFileBig=xIbl5gnghPLprB7Ff3WL1A==, tableContent=null), ArticleFig(id=1210516772676039473, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 3, caption= Binding mode of BIIL260 to leukotriene B<sub>4</sub> receptor 1 (BLT1)<sup>[<a href="javascript:;" class="mag_content_a" onclick="piaofuRef(this,'b21')" rid="b21">21</a>]</sup>. a: Structure of the BIIL260 binding site. BIIL260 and the BLT1 side chains with 4Å from BIIL260 are represented by stick models. Sulfur atoms are colored gold; b: Schematic representation of the BLT1-BIL260 interaction. The salt bridge, hydrogen bonding, and <i>π</i>-to-edge, CH-to-<i>π</i>, and hydrophobic interactions are indicated in red, blue, orange, violet, and green, respectively. The three nonidentical residues in human BLT1 and BLT2, a cognate receptor of BLT1, are highlighted in green shaded boxes and the corresponding residues of human BLT1 and BLT2 (hBLT1 and hBLT2, respectively) are also presented , figureFileSmall=LKiuI1aL6EQpbFF0up8HPw==, figureFileBig=xIbl5gnghPLprB7Ff3WL1A==, tableContent=null), ArticleFig(id=1210516772751536947, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=rDZ4cl76OJm4E0J10esCWw==, figureFileBig=X3933ifse1/1f76Uuc5a0w==, tableContent=null), ArticleFig(id=1210516772806062903, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 4, caption= Structure and binding site of hBLT1<sup>[<a href="javascript:;" class="mag_content_a" onclick="piaofuRef(this,'b22')" rid="b22">22</a>]</sup>. a: Chemical structure of MK-D-046 showing ligand-interacting residues within 4 Å. Critical residues evaluated in our functional and/or binding studies are colored red (polar interactions) or blue (hydrophobic interactions). Hydrogen bonds are shown as dashed red lines; b: Refined <i>2mF</i><sub><i>o</i></sub><i>-DF</i><sub><i>c</i></sub> electron density (gray mesh), contoured at 1.0<i>σ</i>, around MK-D-046 and ligand-interacting residues within 4 Å from MKD-046 , figureFileSmall=rDZ4cl76OJm4E0J10esCWw==, figureFileBig=X3933ifse1/1f76Uuc5a0w==, tableContent=null), ArticleFig(id=1210516772889948985, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=lnZt9UQAJkquoNRYkpcagw==, figureFileBig=ovAywXH3p+BzuyDip1ikTA==, tableContent=null), ArticleFig(id=1210516772948669245, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 5, caption= Ligand binding pocket of BLT1<sup>[<a href="javascript:;" class="mag_content_a" onclick="piaofuRef(this,'b23')" rid="b23">23</a>]</sup>. a: BLT1 ligand binding pocket for LTB<sub>4</sub>. The LTB<sub>4</sub> molecule is shown in magenta in the middle of the pocket, density map of LTB<sub>4</sub> (blue mesh) is set at contour level of 5.0, density map of water (grey mesh) is set at contour level of 4.0, density map of R156<sup>4.64</sup> and R267<sup>7.35</sup> is set at contour level of 4.0. Surrounding residues within 5.0 Å of LTB<sub>4</sub> are shown in sticks and colored in cyan; b: The scheme of the chemical structure of LTB<sub>4</sub> and surround residues , figureFileSmall=lnZt9UQAJkquoNRYkpcagw==, figureFileBig=ovAywXH3p+BzuyDip1ikTA==, tableContent=null), ArticleFig(id=1210516773019972417, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=LeJnwFgmkOjr+vFkW09iqw==, figureFileBig=Eh4EeT0JiTUgpJoW8dFB2w==, tableContent=null), ArticleFig(id=1210516773066109763, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 6, caption= Structures of BIIL-284 (<strong>7</strong>), BIIL-260 (<strong>8</strong>) and BIIL-315 (9) , figureFileSmall=LeJnwFgmkOjr+vFkW09iqw==, figureFileBig=Eh4EeT0JiTUgpJoW8dFB2w==, tableContent=null), ArticleFig(id=1210516773170967365, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=Hw+jTWM98TIoRnq9cZ//ng==, figureFileBig=3lZ6omk4WDBBgM3Qfhm4Tw==, tableContent=null), ArticleFig(id=1210516773296796487, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 7, caption= The structure of CGS-25019C (<strong>10</strong>) , figureFileSmall=Hw+jTWM98TIoRnq9cZ//ng==, figureFileBig=3lZ6omk4WDBBgM3Qfhm4Tw==, tableContent=null), ArticleFig(id=1210516773355516745, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=s5Z6HzvR8NbAU65uCajLFQ==, figureFileBig=6OThQajS1fq6LiDjz9iNgQ==, tableContent=null), ArticleFig(id=1210516773414237003, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 8, caption= Structures of DW-1350 (<strong>11</strong>) and DW-1352 (<strong>12</strong>) , figureFileSmall=s5Z6HzvR8NbAU65uCajLFQ==, figureFileBig=6OThQajS1fq6LiDjz9iNgQ==, tableContent=null), ArticleFig(id=1210516773477151565, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=slrNgHjJZ0YVsHyMxBephw==, figureFileBig=noHv3LQLZ6WnuW4eLX+2DA==, tableContent=null), ArticleFig(id=1210516773552649038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 9, caption= Structures of CP-105696 (<strong>13</strong>), CP-195543 (<strong>14</strong>) and Compd. 38 (<strong>15</strong>) , figureFileSmall=slrNgHjJZ0YVsHyMxBephw==, figureFileBig=noHv3LQLZ6WnuW4eLX+2DA==, tableContent=null), ArticleFig(id=1210516773615563600, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=yMlClOKJUnjocd1Iy5ge5w==, figureFileBig=rpMnEAU0YzCHCLAoKacpTA==, tableContent=null), ArticleFig(id=1210516773716226896, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 10, caption= Structure-activity relationship of CP-105696 , figureFileSmall=yMlClOKJUnjocd1Iy5ge5w==, figureFileBig=rpMnEAU0YzCHCLAoKacpTA==, tableContent=null), ArticleFig(id=1210516773791724369, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=Vq+vvw3gtEOfyIbhVLtoKw==, figureFileBig=iQflquJ9nQTFZyVDjbeL1g==, tableContent=null), ArticleFig(id=1210516773854638931, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 11, caption= Structure-activity relationship of CP-195543 , figureFileSmall=Vq+vvw3gtEOfyIbhVLtoKw==, figureFileBig=iQflquJ9nQTFZyVDjbeL1g==, tableContent=null), ArticleFig(id=1210516773934330708, 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label=Figure 13, caption= Structure-activity relationship of LY-293111 , figureFileSmall=6tqJ+2Lo2m8pSTLGd60r/w==, figureFileBig=qtzorGrg0ZiaITH3SXBAzA==, tableContent=null), ArticleFig(id=1210516774244709208, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=MV9WSMZCn2LSg2khQ5/tyg==, figureFileBig=kyfSu+Wd2FbFI+Dv5hHEFA==, tableContent=null), ArticleFig(id=1210516774316012377, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Figure 14, caption= The structure of Biomed-101 (<strong>35</strong>) , figureFileSmall=MV9WSMZCn2LSg2khQ5/tyg==, figureFileBig=kyfSu+Wd2FbFI+Dv5hHEFA==, tableContent=null), ArticleFig(id=1210516774395704154, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=yv6RHypYC9JL4gCMfEgqng==, 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CompoundPMNLs Kiapp/nmol·L-1Ca2+ Levelc IC50/nmol·L-1CTXd IC50/nmol·L-1
Vital cellsaMembranesb
BIIL-2601.7 ± 0.721.4 ± 0.160.822.90 ± 1.33
BIIL-3151.9 ± 0.141.1 ± 0.320.750.65 ± 0.43
BIIL-284230 ± 98221 ± 19-e-
), ArticleFig(id=1210516774626390877, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Table 1, caption=

Inhibition of LTB4 binding to receptors, LTB4-induced elevation of intracellular calcium levels and chemotaxis by BIIL-260, BIIL-315 and BIIL-284. aInhibition of LTB4 binding to receptors on human polymorphonuclear leukocytes (PMNLs); bInhibition of LTB4 binding to receptors on human PMNLs membranes; cEffect on LTB4-induced elevation of intracellular calcium levels in human neutrophils; dInhibition of LTB4-induced chemotaxis (CTX) of human PMNLs; eNot tested

, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundPMNLs Kiapp/nmol·L-1Ca2+ Levelc IC50/nmol·L-1CTXd IC50/nmol·L-1
Vital cellsaMembranesb
BIIL-2601.7 ± 0.721.4 ± 0.160.822.90 ± 1.33
BIIL-3151.9 ± 0.141.1 ± 0.320.750.65 ± 0.43
BIIL-284230 ± 98221 ± 19-e-
), ArticleFig(id=1210516774710276958, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundMouse ear inflammationa ED50/mg·kg-1Transdermal chemotaxisb ED50/mg·kg-1Neutropeniac ED50/mg·kg-1Mac1-expressiond ED50/mg·kg-1
BIIL-2840.0080.030.0040.05
), ArticleFig(id=1210516774781580127, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Table 2, caption=

Inhibition of LTB4-induced mouse ear inflammation, transdermal chemotaxis, neutropenia and Mac 1-expression in vivo models. aInhibition of LTB4-induced mouse ear inflammation; bInhibition of LTB4-induced transdermal chemotaxis in guinea pigs; cInhibition of LTB4-induced neutropenia in monkeys; dInhibition of LTB4-induced Mac1-expression in monkeys

, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundMouse ear inflammationa ED50/mg·kg-1Transdermal chemotaxisb ED50/mg·kg-1Neutropeniac ED50/mg·kg-1Mac1-expressiond ED50/mg·kg-1
BIIL-2840.0080.030.0040.05
), ArticleFig(id=1210516774882243424, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundPMNa IC50/nmol·L-1CTXb IC50/nmol·L-1CD11b (IC)c IC50/nmol·L-1CD11b (WB)d IC50/nmol·L-1
CP-1056968.4 ± 0.35.0 ± 2.0430 ± 13076 700 ± 104
CP-1955436.8 ± 0.752.4 ± 1.6280 ± 60660 ± 60
Compd. 383.8 ± 3.415 ± 11360 ± 0330 ± 15
), ArticleFig(id=1210516774970323809, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Table 3, caption=

Inhibition of LTB4 binding to receptors and LTB4-induced chemotaxis, CD11b up-regulation on isolated human neutrophils and in whole blood by CP-105696, CP-195543 and Compd. 38. aInhibition of LTB4 binding to receptors on isolated human neutrophils; bInhibition of LTB4-induced chemotaxis of isolated human neutrophils; cInhibition of LTB4-induced CD11b up-regulation on isolated human neutrophils; dInhibition of LTB4-induced CD11b up-regulation in whole blood

, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundPMNa IC50/nmol·L-1CTXb IC50/nmol·L-1CD11b (IC)c IC50/nmol·L-1CD11b (WB)d IC50/nmol·L-1
CP-1056968.4 ± 0.35.0 ± 2.0430 ± 13076 700 ± 104
CP-1955436.8 ± 0.752.4 ± 1.6280 ± 60660 ± 60
Compd. 383.8 ± 3.415 ± 11360 ± 0330 ± 15
), ArticleFig(id=1210516775050015586, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundR1R2R3R4BLT1 cAMP assay EC50/nmol·L-1Isomer
16CF3HH5.33S, 4R or 3R, 4S
17CF3HH9Rac-trans
18CF3HH13S, 4R or 3R, 4S
19CF3HCH363R, 4S
20CF3FH43S, 4R or 3R, 4S
21CF3HH83S, 4R or 3R, 4S
22CF3HH53S, 4R or 3R, 4S
23CF3HH43S, 4R or 3R, 4S
24CF3HH43, 4-trans
), ArticleFig(id=1210516775133901667, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Table 4, caption=

EC50 values of aryl sulfonamides in the BLT1 cAMP assay

, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundR1R2R3R4BLT1 cAMP assay EC50/nmol·L-1Isomer
16CF3HH5.33S, 4R or 3R, 4S
17CF3HH9Rac-trans
18CF3HH13S, 4R or 3R, 4S
19CF3HCH363R, 4S
20CF3FH43S, 4R or 3R, 4S
21CF3HH83S, 4R or 3R, 4S
22CF3HH53S, 4R or 3R, 4S
23CF3HH43S, 4R or 3R, 4S
24CF3HH43, 4-trans
), ArticleFig(id=1210516775221982052, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundR1R2R3BLT1 cAMP assay EC50/nmol·L-1Isomer
25CF3F63S, 4R or 3R, 4S
26F43S, 4R or 3R, 4S
27F43S, 4R or 3R, 4S
28F23S, 4R or 3R, 4S
29H93S, 4R or 3R, 4S
30CF3F9Rac-trans
31H33S, 4R or 3R, 4S
32H53S, 4R or 3R, 4S
), ArticleFig(id=1210516775289090917, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Table 5, caption=

EC50 values of aryl acylsulfonamides in the BLT1 cAMP assay

, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundR1R2R3BLT1 cAMP assay EC50/nmol·L-1Isomer
25CF3F63S, 4R or 3R, 4S
26F43S, 4R or 3R, 4S
27F43S, 4R or 3R, 4S
28F23S, 4R or 3R, 4S
29H93S, 4R or 3R, 4S
30CF3F9Rac-trans
31H33S, 4R or 3R, 4S
32H53S, 4R or 3R, 4S
), ArticleFig(id=1210516775385559910, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundArAr1XHL-60 IC50/nmol·L-1Neutrophil chemotaxis IC50/nmol·L-1Ca2+ mobilization IC50/nmol·L-1
hBLT1hBLT2
37N0.481.8205.03 060.0
38CH0.21-a38.5628.0
39CH0.07-71.0143.0
40CH0.440.10114.0164.0
41CH1.193.68129.0194.0
), ArticleFig(id=1210516775440085863, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Table 6, caption=

Antagonists activity at BLT1 receptors expressed in an HL-60 cell line, LTB4-evoked chemotaxis of human neutrophils and Ca2+ mobilization assay by compounds with X, R1 and R2 modifications. aNot tested

, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundArAr1XHL-60 IC50/nmol·L-1Neutrophil chemotaxis IC50/nmol·L-1Ca2+ mobilization IC50/nmol·L-1
hBLT1hBLT2
37N0.481.8205.03 060.0
38CH0.21-a38.5628.0
39CH0.07-71.0143.0
40CH0.440.10114.0164.0
41CH1.193.68129.0194.0
), ArticleFig(id=1210516775507194728, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundPhaseCondition or diseaseClinical trial ID & status
BIIL-284ⅠHealthyNCT02265302 (1998.12)
NCT02266550 (1999.10)
NCT02273414 (1999.12)
NCT02265653 (1999.12)
NCT02273427 (2000.03)
NCT02268149 (2000.07)
NCT02273440 (2000.07)
NCT02265640 (2000, 12)
NCT02265666 (2001.11)
Rheumatoid arthritisNCT02247375 (2000.05)
Hepatic insufficiencyNCT02265627 (2000.09)
Cystic fibrosisNCT02265679 (2002.07)
NCT02269189 (2002.11)
ⅡCOPDNCT02249338 (2000.04)
NCT02249247 (2002.08)
AsthmaNCT02249312 (2000.04)
Rheumatoid arthritisNCT02251210 (2002.11)
Cystic fibrosisNCT00060801 (2004.07)
CGS-25019CⅡCOPD[42]No Clinical trial ID
DW-1350
DW-1352		Preclinical[44]--
CP-105696ⅠHealthy[49]No Clinical trial ID
CP-195543ⅡRheumatoid arthritisNCT00424294 (2008.02)
LY-293111ⅠUnspecified adult solid tumor[54]NCT00006375 (2003.02)
ⅡPancreatic cancer[63]NCT00055250 (2005.10)
Non-small cell lung cancer[64]NCT00069875 (2005.12)
Stable plaque psoriasis[65]No Clinical trial ID
Biomed-101ⅠKidney cancerNCT00004890 (2002.12)
ONO-4057Ⅰ[66]-No Clinical trial ID
), ArticleFig(id=1210516775574303593, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1210516751104733742, language=CN, label=Table 7, caption=

Summary of LTB4 receptor antagonists in clinical trials. COPD: Chronic obstructive pulmonary disease

, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundPhaseCondition or diseaseClinical trial ID & status
BIIL-284ⅠHealthyNCT02265302 (1998.12)
NCT02266550 (1999.10)
NCT02273414 (1999.12)
NCT02265653 (1999.12)
NCT02273427 (2000.03)
NCT02268149 (2000.07)
NCT02273440 (2000.07)
NCT02265640 (2000, 12)
NCT02265666 (2001.11)
Rheumatoid arthritisNCT02247375 (2000.05)
Hepatic insufficiencyNCT02265627 (2000.09)
Cystic fibrosisNCT02265679 (2002.07)
NCT02269189 (2002.11)
ⅡCOPDNCT02249338 (2000.04)
NCT02249247 (2002.08)
AsthmaNCT02249312 (2000.04)
Rheumatoid arthritisNCT02251210 (2002.11)
Cystic fibrosisNCT00060801 (2004.07)
CGS-25019CⅡCOPD[42]No Clinical trial ID
DW-1350
DW-1352		Preclinical[44]--
CP-105696ⅠHealthy[49]No Clinical trial ID
CP-195543ⅡRheumatoid arthritisNCT00424294 (2008.02)
LY-293111ⅠUnspecified adult solid tumor[54]NCT00006375 (2003.02)
ⅡPancreatic cancer[63]NCT00055250 (2005.10)
Non-small cell lung cancer[64]NCT00069875 (2005.12)
Stable plaque psoriasis[65]No Clinical trial ID
Biomed-101ⅠKidney cancerNCT00004890 (2002.12)
ONO-4057Ⅰ[66]-No Clinical trial ID
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白三烯B4受体拮抗剂的研究进展
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赵甜甜 , 沈珑瑛 , 潘显道 *
药学学报 | 综述 2022,57(10): 3133-3145
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药学学报 | 综述 2022, 57(10): 3133-3145
白三烯B4受体拮抗剂的研究进展
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赵甜甜, 沈珑瑛, 潘显道*
作者信息
  • 中国医学科学院、北京协和医学院药物研究所, 北京 100050

通讯作者:

*潘显道, Tel: 86-10-63166764, E-mail:
Research progress of leukotriene B4 receptor antagonists
Tian-tian ZHAO, Long-ying SHEN, Xian-dao PAN*
Affiliations
  • Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
出版时间: 2022-10-12 doi: 10.16438/j.0513-4870.2022-0602
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摘要
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白三烯B4 (leukotriene B4, LTB4) 是一种促炎调节因子, 多数炎症细胞均可产生。LTB4与其受体BLT1 (leukotriene B4 receptor 1) 结合后可通过趋化作用和黏附分子上调将嗜中性粒细胞和巨噬细胞迁移至炎症部位。大量研究表明LTB4-BLT1轴与自身免疫性疾病及炎症的发生有关。因此, LTB4受体拮抗剂对治疗这类疾病具有重要作用。本文简略描述了LTB4的作用, 综述了目前处于临床或临床前研究的LTB4受体拮抗剂的研究进展。

白三烯B4  /  拮抗剂  /  构效关系

Leukotriene B4 (LTB4) is a proinflammatory lipid mediator that is synthesized by a number of inflammatory cells. Binding of LTB4 to its receptor leukotriene B4 receptor 1 (BLT1) can migrate neutrophils and macrophages to inflammatory sites through chemotaxis and up-regulation of adhesion molecules. Many researches have shown that LTB4-BLT1 axis is related to the occurrence of autoimmune disorders and other inflammatory diseases. Receptor antagonists of LTB4 are thus expected to be useful therapeutics for these diseases. In this review, we briefly describe the biological function of LTB4 and summarize the preclinical and clinical developments of LTB4 receptor antagonists.

leukotriene B4  /  antagonist  /  structure-activity relationship
赵甜甜, 沈珑瑛, 潘显道. 白三烯B4受体拮抗剂的研究进展. 药学学报, 2022 , 57 (10) : 3133 -3145 . DOI: 10.16438/j.0513-4870.2022-0602
Tian-tian ZHAO, Long-ying SHEN, Xian-dao PAN. Research progress of leukotriene B4 receptor antagonists[J]. Acta Pharmaceutica Sinica, 2022 , 57 (10) : 3133 -3145 . DOI: 10.16438/j.0513-4870.2022-0602
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白三烯B4 (leukotriene B4, LTB4) 是一种促炎调节因子(图 1), 由花生四烯酸(arachidonic acid, AA) 经5-脂氧合酶(5-lipoxygenase, 5-LO) 代谢途径产生[1, 2]。
炎症刺激后, Ca2+内流, 激活胞浆型磷脂酶A2 (cytosolic phospholipase A2, cPLA2), 使其从胞质转移到细胞膜的磷脂层。在cPLA2催化下, AA从膜磷脂中释放出来[3], 在5-LO作用下, 5位氧化得到5-羟基过氧化二十碳四烯酸(5-hydroperoxyeicosatetraenoic acid, 5-HPETE)。5-HPETE随后转化为环氧化物LTA4, 水解后生成LTB4[4, 5] (图 2)。其主要功能是活化和募集嗜中性粒细胞、巨噬细胞等, 具有很强的生物活性[6]。大量研究表明LTB4主要参与炎症、免疫反应等, 在类风湿性关节炎[7] (rheumatoid arthritis, RA)、哮喘[8]等疾病中发挥了重要作用。
除5-LO代谢途径外, AA也可以通过环氧合酶(cyclooxygenase, COX) 途径代谢。在COX作用下, AA代谢生成前列腺素G2 (prostaglandin G2, PGG2), 经前列腺素氢过氧化物酶催化生成PGH2 (prostaglandin H2, PGH2), 然后在各种特异性前列腺素合成酶作用下产生各种前列腺素, 或在凝血噁烷合成酶作用下生成血栓烷A2 (thromboxane A2, TXA2)[9]。
非甾体类抗炎药(non-steroidal anti-inflammatory drugs, NSAIDs) 针对的靶点即为COX[10], 但此类化合物不良反应明显[11, 12]。非选择性NSAIDs轻则引起胃肠道不适, 重则引发胃溃疡和胃十二指肠穿孔、出血。此外, NSAIDs会增加患心血管疾病的风险。研究发现AA的两种代谢途径之间存在拮抗作用。当抑制了环氧合酶途径后, 相应地会促进脂氧合酶代谢[13, 14], 导致促炎介质的产生, 引起不良反应[15]。促进5-LO途径代谢进而会导致LTB4增加, 而LTB4在哮喘、过敏性鼻炎、慢性阻塞性肺炎等疾病的生成过程中发挥着重要作用。因此, 研发有效的LTB4受体拮抗剂是非常有必要的。
本文综述了LTB4及其受体的结构与功能, 以及目前处于临床或临床前研究的LTB4受体拮抗剂的研究进展。
1 LTB4受体简介
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LTB4一旦在细胞质中合成, 就会被释放到胞外, 与细胞表面受体结合, 以自分泌或旁分泌的方式发挥作用[16]。LTB4具有两个受体: BLT1和BLT2。两种受体均为G蛋白偶联受体, 其主要区别在于细胞分布及与LTB4的亲和力[17]。
1.1 BLT1
BLT1是LTB4的高亲和力受体, 主要在白细胞中表达, 包括嗜中性粒细胞、单核细胞、淋巴细胞、巨噬细胞等[18]。此外, 在部分其他细胞中也有表达, 如内皮细胞[19]、上皮细胞[20]、纤维原细胞等。
1.1.1 BLT1的结构
2018年, Hori等[21]报道了BLT1抑制剂BIIL260与gpBLT1的共晶结构(图 3)。晶体结构显示: BIIL260与BLT1之间存在盐桥作用、氢键作用、π-to-edge、CH-to-π和疏水作用。大多数G蛋白偶联受体与7个跨膜结构域内保守的Asp2.50形成以Na+为中心的水簇稳定在非活性状态。BIIL260含有苄脒的结构, 3个苯环结合在正性结合位点, 苄脒占据了Na+水簇的位置并与D662.50相互作用, 模拟了整个以Na+为中心的水簇, 从而抑制BLT1活化。
2021年, Michaelian等[22]报道了MK-D-046与hBLT1的共晶结构(图 4)。结果显示R156、H94均可以和MK-D-046形成氢键作用, 是结合的关键氨基酸。将H94突变为苯丙氨酸或酪氨酸, 活性丧失。除此之外, H94对hBLT1、hBLT2的选择性至关重要。I271、C97、Y237可与MK-D-046之间形成疏水作用。I271、Y237突变导致LTB4效价下降250~400倍, 因此推测LTB4与氨基酸残基之间形成的疏水作用与BLT1/2的选择性有关。将hBLT1与gpBLT1进行比较后发现, 残基构象的差异可能会导致化合物针对两个不同物种BLT1的效价发生颠倒。MK-D-046虽然没有向下延伸至Na+水簇的位置, 但hBLT1的Na+位点保留了与gpBLT1的Na+位点类似的构象。将MK-D-046类似物与hBLT1进行分子对接, 结果显示磺酰基部分的取代基越大, 越有利于将羰基磺酰胺固定在与H943.29和R1564.64相互作用最佳的方向上。磺酰胺对位氟取代可深入到含有F742.60和L782.64的疏水口袋中, 将氟原子去除, 结合能力下降。改变C-4羟基手性, 活性显著下降。
2022年, Wang等[23]报道了LTB4-hBLT1的共晶结构(图 5), 揭示了LTB4激活受体的机制。激动剂和拮抗剂结合的关键区别是直接和间接的极性相互作用。拮抗剂MK-D-046与R1564.64、H943.29直接形成氢键作用, 而LTB4则是通过水分子与R1564.64、H943.29形成氢键网络。共晶结构显示水分子和关键极性残基的氢键作用是LTB4与受体结合的决定因素。N2687.36与C-1羧基之间存在直接的极性相互作用, 以及连接LTB4与受体关键残基的水分子簇。水分子1 (W1) 通过氢键将R1564.64、R2677.35与C-5羟基连接起来。水分子2 (W2) 与R2677.35也形成氢键作用。水分子6 (W6) 与N2687.36、水分子7 (W7) 之间形成氢键。这些水分子将极性残基N2687.36、R1564.64、R2677.35和H943.29与LTB4通过氢键连接起来, 从而将配体锁在口袋里。
将激动剂LTB4与拮抗剂MK-D-046的结合口袋进行对比发现二者的结合几乎没有变化。M1013.36和I2717.39在激动剂结合和拮抗剂结合之间表现出最显著的不同, M1013.36A和I2717.39A突变体均表现出受体活性的显著丧失。BLT1激活的关键机制是M1013.36和I2717.39残基移位到受体中心, 阻止Na+进入到口袋下部, 解锁了口袋下部的离子锁。
与其他脂质受体相比, BLT1的特点是具有细胞外侧的大开口。具有一个广泛开放的配体结合袋可能是目前BLT1靶向药物设计缺乏特异性和有效性的原因。
1.1.2 LTB4-BLT1轴的生理功能及病理作用
LTB4-BLT1轴通过不同的细胞机制参与不同的炎症和炎症反应的不同阶段[24]。在早期炎症反应中, LTB4-BLT1轴的主要作用是募集免疫细胞。在T细胞介导的炎症反应中, LTB4-BLT1轴可以介导效应T细胞到炎症组织[25-28]。在调节B细胞功能方面, Nagatake等[29]发现在B细胞分化为IgA(+) B细胞和小肠固有层浆细胞时, BLT1表达。BLT1通过诱导髓样分化因子88 (myeloid differentiation factor 88, MyD88) 增强了共生菌依赖IgA(+) 浆细胞的增殖, 从而在抗原特异性肠道IgA的产生中发挥关键作用。Subramanian等[30]研究了LTB4-BLT1轴在血管内中性粒细胞免疫应答中传递趋化信号的机制。动物实验结果显示LTB4信号通路协调非肌球蛋白IIA和β2-整合素的动态再分配, 从而促进中性粒细胞的阻滞和外渗。
在其他组织细胞中, LTB4-BLT1轴可以影响细胞的生理功能, 从而导致病理性炎症。因此, 阻断LTB4-BLT1轴可抑制病理性炎症进程或缓解炎症反应。
LTB4是导致慢性阻塞性肺炎的主要促炎介质。Zhang等[31]研究发现BLT1抑制剂U75302可降低小鼠肺泡巨噬细胞溶酶体和自噬体数量, 并可能增强转录因子EB (transcription factor-EB, TFEB) 的转录激活表达, 通过诱导自噬改善炎症反应。Dong等[32]发现细胞因子信号转导抑制因子1 (suppressor of cytokine signaling 1, SOCS1) 在慢性阻塞性肺炎患者肺组织中表达显著降低, 而BLT1抑制剂在体外可恢复SOCS1的表达, 进而抑制炎症细胞因子的分泌。
Xiong等[20]研究发现, BLT1在小鼠上皮细胞或正常人支气管上皮细胞(normal human bronchial epithelial, NHBE) 中表达, 木瓜蛋白酶通过NHBE诱导LTB4释放, 进而通过BLT1激活蛋白激酶B (protein kinase B, PKB) 扩增白介素-33 (interleukin-33, IL-33)。致敏期LTB4-BLT1轴中断显著降低IL-33的表达, 降低2型先天性淋巴细胞(group II innate lymphoid cells, ILC2) 激活和树突状细胞(dendritic cells, DCs) 迁移, 从而削弱过敏辅助型T细胞2 (T helper 2 cell, Th2) 反应。
Zhou等[33]发现LTB4-BLT1轴通过控制树突状细胞促炎调节因子的产生及Th1、Th17的分化促进结肠炎的发展。机制研究显示BLT1通过PLCβ-PKC信号通路(phospholipase C beta-protein kinase C signaling) 调节促炎细胞因子的产生。BLT1抑制剂可减少人外周血中树突状细胞产生的促炎细胞因子。
Miyabe等[7]研究发现C5a-C5aR通路(complement component 5a-complement 5a receptor pathway) 诱导中性粒细胞产生LTB4, 而免疫复合物(immune complexes, ICs) 通过Fcγ受体(Fc receptor gamma, FcγR) 活化诱导中性粒细胞产生白介素1β (interleukin-1β, IL-1β)。在RA发生的早期阶段, BLT1介导第一批中性粒细胞进入关节。动物实验表明, BLT1或5-LO缺陷大鼠对RA完全耐受。用CP-105696 (BLT1抑制剂) 或L-739010 (5-LO抑制剂) 预处理可显著抑制RA的发生。治疗给药也可显著改善RA大鼠关节的破坏程度。
Bouchareychas等[34]研究了LTB4-BLT1轴在滑膜炎及破骨细胞分化中的作用。结果显示, BLT1缺乏导致破骨细胞相关基因上调, 并增加能够形成F-actin环的巨型多核TRAP(+)细胞的形成。此外, BLT1缺乏使破骨细胞中磷酸化的NF-κB和IκB水平升高。数据显示, LTB4-BLT1轴在体内加剧滑膜炎症状。
Lv等[35]实验发现LTB4-BLT1轴在博来霉素诱导的肺纤维化急性损伤期发挥了关键作用, 早期中断LTB4-BLT1轴可以防止组织纤维化的后期发展。BLT1抑制剂U75302在小鼠急性损伤期处理后, 可显著减弱肺纤维化, 并伴有早期浸润中性粒细胞、晚期浸润CD4+ T细胞显著减少。
Asahara等[36]发现BLT1的缺失可减轻足底福尔马林损伤后的外周炎症和脊髓伤害性感受过程。数据表明, LTB4-BLT1轴不仅参与外周炎症反应, 还参与足底注射福尔马林诱导的脊髓神经元激活。LTB4-BLT1信号是治疗干预组织损伤引起的急性和持续性疼痛的潜在靶点。
1.2 BLT2
BLT2是LTB4的低亲和力受体, 普遍分布于白细胞、脾脏、肝、卵巢等。研究发现12-HHT [12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid] 与BLT2的亲和力远高于LTB4, 是BLT2的高亲和力内源性配体[17, 37]。目前, BLT2的结构尚不清楚。因为BLT2与LTB4的亲和力远小于BLT1与LTB4的亲和力, 因此BLT2对LTB4发挥作用的影响远小于BLT1。
2 LTB4受体拮抗剂
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目前报道的LTB4受体拮抗剂的设计思路均是基于配体的药物设计, 骨架均与LTB4具有相似之处。根据其结构可分为两类: 苄脒类和羧酸类。
2.1 苄脒类
2.1.1 BIIL-260
BIIL-284是前药, 在体内可代谢为具有活性的BIIL-260、BIIL-315 (图 6)。两个代谢活化产物均对LTB4受体具有高亲和力。BIIL-260是BLT1和BLT2双重抑制剂。
体外实验表明, BIIL-260和BIIL-315可以抑制LTB4介导的人中性粒细胞的趋化性, 也可以抑制由LTB4诱导的Ca2+释放(表 1)。动物实验表明, BIIL-284是一种有效的长效口服LTB4受体拮抗剂(表 2)[38]。
但在临床试验中, BIIL-284的表现不佳。2004年, Alten等[39]探讨了口服BIIL-284对RA患者外周血白细胞中LTB4诱导的Mac-1 (CD11b/CD18) 表达的抑制作用。试验共有26名RA患者参与, 分为3组, 分别给予BIIL-284 25、150 mg或安慰剂。结果显示25和150 mg剂量的BIIL-284均能安全有效地抑制中性粒细胞Mac-1的表达。因此, 较长时间的BIIL-284治疗可能会给RA患者带来临床效益。2007年, Diaz-Gonzalez等[40]使用BIIL-284治疗RA, 研究对象为持续3个月的RA患者, 共有342名患者随机接受了5、25、75 mg BIIL-284或安慰剂治疗。结果显示治疗组与安慰剂组之间并无明显的统计学差异。该临床试验表明, 口服BIIL-284的RA患者, 炎症只能得到适度改善。2014年Konstan等[41]报道了BIIL-284 BS治疗囊胞性纤维症(cystic fibrosis, CF) 的Ⅱ期临床试验结果。中期分析显示接受BIIL-284 BS的成人肺部相关严重不良事件的发生率显著增加, 试验终止。该结果表明过度抑制炎症反应可能会增加感染相关不良反应的发生。
2.1.2 CGS-25019C
CGS-25019C (图 7) 是一种有效的LTB4受体可逆拮抗剂, 是一种高度特异性的中性粒细胞功能拮抗剂。体外研究表明CGS-25019C选择性结合BLT1, 可以抑制LTB4受体结合(IC50 = 4 nmol·L-1), 也可以有效抑制中性粒细胞脱粒(IC50 = 0.04 nmol·L-1)[42]。体内实验结果显示, CGS-25019C抑制小鼠耳水肿形成和髓过氧化物酶(myeloperoxidase, MPO) 引起的中性粒细胞内流的ED50分别为1.4和1.2 mg·kg-1。单次口服18 h后测定小鼠水肿情况和MPO活性, 其ED50分别为5.7和7.7 mg·kg-1。口服给药后测定不同时间段CGS-25019C对LTB4诱导的大鼠中性粒细胞减少症的抑制作用, 前4 h其ED50为4 mg·kg-1, 18 h后ED50为11 mg·kg-1 [43]。
2007年Ⅱ期临床试验采用CGS-25019C治疗慢性阻塞性肺病(chronic obstructive pulmonary disease, COPD), 共有24名患者参与。结果显示治疗组和安慰剂组之间痰中性粒细胞百分比、总细胞计数、MPO、IL-8和TNF-α水平无显著差异[42]。
2.1.3 DW-1350和DW-1352
DW-1350和DW-1352 (图 8) 均为LTB4受体抑制剂。研究发现LTB4可以通过产生破骨细胞刺激骨吸收[44]。3-氨基-1, 2-苯并异噁唑衍生物在对LTB4受体发挥拮抗作用的同时, 对骨质疏松症的预防和治疗是有效的。体外实验表明, DW-1350和DW-1352抑制破骨细胞增殖的IC50分别为19.87、1.25 nmol·L-1, 抑制破骨细胞融合的IC50分别为0.81、0.74 μmol·L-1, 抑制破骨细胞的骨重吸收的IC50分别为0.075、0.131 μmol·L-1。DW-1350和DW1352均能影响成骨细胞的分化和形成, 可用于治疗骨质疏松[45]。体内实验结果显示, DW-1350MSA对于预防固定性骨质疏松具有良好的作用, 对卵巢切除术引起的雌激素缺乏性骨质疏松具有良好的预防作用[46]。目前尚未开展临床试验。
2.2 羧酸类
2.2.1 CP-105696和CP-195543
CP-105696 (图 9) 是一种结构新颖、对BLT1具有高选择性亲和力的LTB4受体拮抗剂。体外实验表明, CP-105696显著抑制[3H]LTB4与人嗜中性粒细胞的LTB4受体结合, 抑制人嗜中性粒细胞的趋化性(表 3)[47]。动物实验显示, CP-105696抑制LTB4诱导的小鼠皮肤中性粒细胞内流的ED50为4.2 mg·kg-1。CP-105696在0.3~10 mg·kg-1剂量下对RA小鼠的临床症状和组织学变化均有显著影响。如果在RA发作前或整个实验过程中开始药物治疗, 同样有效[48]。
临床研究表明CP-105696在低蛋白环境中表现出对LTB4受体的高亲和力。但在全血中, 与血浆蛋白的结合力强, 使得给药剂量大幅增加。Ⅰ期临床试验共有48名受试者参与, 在受试者尿液中检测到小于1%的原药, 表明该化合物的主要排泄方式是胆汁排泄。因此CP-105696半衰期过长的可能原因是高蛋白结合率和肝肠循环相结合[49]。
CP-105696的构效关系研究显示(图 10): 吡喃环替换为环己烷后, 活性下降, 水溶性降低; 替换为环戊烷后, 活性显著降低。3位4-苯基苄基取代活性最强, 4′位其他取代基取代活性均显著下降; 联苯基与吡喃环之间的距离变远后, 活性下降。3, 4位相对构型为反式时具有活性, 右旋体活性高于左旋体。7位酸性基团是活性必需基团。除羧基外, 四氮唑取代也具有活性。
Pfizer对C-7位环状羧基和链状羧基进行计算, 结果显示, 羧基处于平面的上方或下方更有优势。因此, 采用苯甲酸将羧基的空间位置固定, 得到化合物CP-195543[50]。
与CP-105696相比, CP-195543体外活性略有提高, 在全血中与血浆蛋白的结合率较CP-105696显著下降。但CP-195543失去了对受体的选择性, 是BLT1和BLT2的双重抑制剂。动物实验表明, CP-195543在大鼠和猴体内的半衰期为10~15 h, 代谢途径主要有两种: 葡萄糖醛酸化、氧化[51]。在Ⅱ期临床试验中, 将CP-195543与塞来昔布合用治疗RA, 最终因耐受性差和停药率高提前终止试验。
初步构效关系研究显示, 将CP-195543羧基替换为磺酰胺基后得到的Compound 38活性保持且与血浆蛋白的结合率显著下降。据此, Han等[52, 53]合成了一系列磺酰胺类(表 4) 及羰基磺酰胺类(表 5) 化合物。
CP-195543的构效关系研究显示(图 11): 2′位-COOH被-NHSO2CF3取代后, 活性可以维持, 血浆蛋白结合率较CP-195543进一步下降。磺酰基上大基团取代有利于磺酰胺固定在与蛋白结合的最佳取向。5′位吸电子基取代较给电子基取代活性显著提高。4′′位苯环取代后, 活性显著提高, 血浆蛋白结合率也随之提高, 其他取代基取代活性下降。
2.2.2 LY-293111
LY-293111 (图 12) 是BLT1受体抑制剂, 也是5-LO抑制剂和过氧化物酶体增殖物激活受体(peroxisome proliferators-activated receptor-γ, PPARγ) 激动剂。体外实验表明, LY-293111具有抑制人类嗜中性粒细胞趋化的作用(IC50 = 17.6 ± 4.8 nmol·L-1), 也可以抑制LTB4诱导的Ca2+释放(IC50 = 20 nmol·L-1)。动物实验表明LY-293111具有潜在的抗炎活性。
Ⅰ期临床结果表明LY-293111可安全口服, 不良反应轻微[54]。Ⅱ期临床试验主要针对抗炎和抗癌两个方面。抗炎方面, 在银屑病的临床试验中发现LY-293111并不能有效地防止银屑病的复发。抗癌方面, IIIB/IV期非小细胞肺癌患者被随机分为3组, 接受LY293111 (200 mg每日两次、600 mg每日两次) 或安慰剂治疗7天, 同时服用顺铂和吉西他滨。结果显示各治疗组的中位存活期(progression-free survival, PFS) 无显著差异。LY-293111联合吉西他滨-顺铂与安慰剂联合吉西他滨-顺铂相比, 未增加非小细胞肺癌患者的中位PFS[55]。LY-293111与吉西他滨联用治疗晚期胰腺癌, 133位患者随机分为两组, 接受LY-293111与吉西他滨联用治疗或安慰剂与吉西他滨治疗。结果显示两组6个月存活率无明显差异。LY-293111与吉西他滨联用对治疗晚期胰腺癌无益[56]。
LY-293111是由LY-255283经过结构优化获得的。LY-255283的结构可分为3部分: 亲脂部位、亲水部位和中间连接链。对亲脂部位研究发现, 将LY-255283的甲基酮替换为烷氧基或烷基, 活性提高, 但口服活性不佳。亲脂部位倾向于取共平面结构。苯环取代时, 苯环上有吸电子基或供电子基均具有活性。亲水部位进行结构改造发现LY-255283的丙酸结构对活性具有重要影响。在具有酸性基团的同时其他部位含有碱性基团对活性没有太大影响(图 13)。有趣的是, 当亲水性部位有两个羧基取代时, 特异性作用于肺部, 吸入给药最佳。对中间连接原子的研究发现3个碳原子活性最佳[57]。
LY-293111的主要代谢途径为羟基和羧基的葡萄糖醛酸化, 口服生物利用度小于25%, 会发生肝肠循环[58]。
2.2.3 Biomed-101
Biomed-101 (图 14) 是BLT1和BLT2的双重抑制剂。用于减轻肾癌和黑色素瘤患者使用IL-2后的不良反应, 临床试验已验证其安全性, 其他试验尚未开展。
2.2.4 ONO-4057
ONO-4057 (图 15) 是BLT1和BLT2的双重抑制剂。体外实验显示ONO-4057抑制LTB4与受体结合的Ki为3.7 ± 0.9 nmol·L-1, 抑制LTB4诱导的游离钙值升高的IC50为0.7 ± 0.3 μmol·L-1, 抑制人中性粒细胞聚集、趋化或脱颗粒的IC50分别为3.0 ± 0.1、0.9 ± 0.1和1.6 ± 0.1 μmol·L-1。在体内研究中, 口服ONO-4057可防止豚鼠LTB4诱导的瞬时中性粒细胞减少或皮内中性粒细胞迁移(ED50 = 25.6或5.3 mg·kg-1)[59]。ONO-4057联合他克莫司预处理对大鼠肝脏缺血再灌注损伤模型具有叠加作用[60]。
Ⅰ期临床研究显示ONO-4057可抑制LTB4诱导的Ca2+释放, 可用来治疗溃疡性结肠炎、牛皮癣和哮喘等[61]。1997年, 该药物停止Ⅱ期临床研究。
2010年, Goodnow等[62]进一步优化并研究其构效关系发现, Ar与Ar1的大小对活性具有重要影响, 苯并亚甲二氧基取代可能存在其特殊的结合作用(表 6)。
3 临床试验效果不佳的原因
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目前大多数的LTB4受体拮抗剂在临床前研究中均表现出良好的药理活性, 但在临床试验中均表现不佳(表 7[42, 49, 54, 63-66])。其可能的原因有: ①部分化合物缺乏特异性, BLT1与BLT2的功能可能相反, 因此BLT1和BLT2的双重抑制剂在体内缺乏作用; ②临床患者的选择不当。大多数炎症人群是异质性的, 有多种调节因子参与。因此, LTB4可能并不在所有的患者中起作用。
4 总结与展望
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LTB4是一种强有力的诱导剂和细胞趋附剂, 作为炎症的重要介质, 其作用已经越来越受到重视。在组织细胞中, LTB4-BLT1轴可导致RA、哮喘等多种疾病产生。
大量的研究工作已经证明BLT1抑制剂对RA等疾病具有明显的治疗作用。此外, 有研究发现LTB4受体拮抗剂与抗癌药物联用, 可增强抗癌药物的有效性[67-69]。但目前已发现的化合物在临床试验中均效果不佳, 目前尚未有理想的药物上市。
在BLT1结构报道之前, LTB4受体拮抗剂的设计均为基于配体的药物设计, 缺乏特异性, 这可能是导致之前药物设计失败的原因之一。随着对LTB4及其受体研究的不断深入, 目前内源性配体LTB4-hBLT1的共晶结构, LTB4受体拮抗剂BIIL260-gpBLT1和MK-D-046-hBLT1的共晶结构均已被报道。激动剂结合与拮抗剂结合的共晶结构对比发现, M1013.36和I2717.39在二者结合时处于不同的位置, 这是化合物发挥激动作用或拮抗作用的关键。此外, 拮抗剂可以与BLT1直接形成氢键作用, 而LTB4通过水分子与受体形成动态氢键网络。
已有化合物的构效关系研究、BLT1结构及其激动机制的揭示为基于结构的LTB4受体拮抗剂的设计提供了基础。但是, 由于BLT2的结构及其功能的研究目前还较为有限, 因此, 发现特异性的BLT1抑制剂仍面临一定的挑战。对BLT2的结构生物学研究将有利于进一步区别BLT1与BLT2, 发现理想的LTB4受体拮抗剂需要多学科的共同努力。
作者贡献: 赵甜甜撰写论文初稿; 沈珑瑛、潘显道修改论文并定稿。
利益冲突: 本文无相关利益冲突。
基金
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  • 中国医学科学院医学与健康科技创新工程项目(2021-1-I2M-028)
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2022年第57卷第10期
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doi: 10.16438/j.0513-4870.2022-0602
  • 接收时间：2022-05-18
  • 首发时间：2025-12-24
  • 出版时间：2022-10-12
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  • 收稿日期：2022-05-18
  • 修回日期：2022-06-14
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中国医学科学院医学与健康科技创新工程项目(2021-1-I2M-028)
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    中国医学科学院、北京协和医学院药物研究所, 北京 100050

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2种不同金属材料的力学参数
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genus		 种数
Number of
species		 占总种数比例
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total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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