[生物医药论文精品a]胆固醇酯转移蛋白抑制剂的研究进展

1胆固醇酯转移蛋白抑制剂的研究进展朱荣芳，郭长彬（首都师范大学化学系，北京100048）摘要目的概述近几年来胆固醇酯转移蛋白CETP抑制剂的研究进展。方法整理并归纳近年来国内外相关文献。结果与结论血浆中CETP活性与冠心病发病率呈负相关，对CETP的抑制可能成为控制冠心病的一个重要的潜在靶标，因此CETP抑制剂的研发将成为治疗冠心病的很有前景的方向。关键词胆固醇酯转移蛋白抑制剂；冠心病；综述A1A0A2A3A4A6A7A5A8A9A10A6A7A11A12A4A6PROGRESSINTHESTUDYOFTHECHOLESTERYLESTERTRANSFERPROTEININHIBITORSZHURONGFANG，GUOCHANGBINDEPARTMENTOFCHEMISTRY,CAPITALNORMALUNIVERSITY,BEIJING100048,CHINAABSTRACTOBJECTIVETOREVIEWTHEPROGRESSOFTHEINHIBITORSOFTHECHOLESTERYLESTERTRANSFERPROTEINCETPINRECENTYEARSMETHODTOSUMMARIZETHERECENTREFERENCESABOUTCETPINHIBITORSFROMINTERNALANDOVERSEASRESULTSANDCONCLUSIONSTHEREISANEGATIVECORRELATIONBETWEENTHEACTIVITYOFCETPINPLASMAANDTHEINCIDENCEOFCORONARYHEARTDISEASECHD,THUSTHECETPINHIBITORSWERECONSIDEREDASTHEPOTENTIALDRUGSTOTREATANDPREVENTCHDKEYWORDSCHOLESTERYLESTERTRANSFERPROTEINCETPINHIBITORSCORONARYHEARTDISEASECHDREVIEW冠状动脉粥样硬化性心脏病也称冠心病CORONARYHEARTDISEASE,CHD，是由于冠状动脉粥样硬化、痉挛等因素造成的冠状动脉狭窄甚至完全堵塞，从而引起心肌供血、供氧不足，产生心绞痛乃至心肌梗死等临床症状的疾病。流行病学G2656临床G16809G20576G5062G16789G4466，血G14038G19568G11873是G16837发CHD的G7380重要G2373G19517因素，而血G14038G19568G11873中G7380关G19202的是G1314G4506G5242G14038蛋白胆固醇LOWDENSITYLIPOPROTEINCHOLESTEROL,LDLCG2331G20652G2462G20652G4506G5242G14038蛋白胆固醇G708HIGHDENSITYLIPOPROTEINCHOLESTEROL,HDLCG709G19489G1314。对冠状动脉疾病来G16840，G1314G8712G5191的HDLC是一个重要的G2373G19517因素1，G2331G20652HDLC的G8712G5191要G8616G19489G1314LDLC的G8712G5191G7368能G1955G4581冠脉疾病的发生，因此近年来G62382G2331G20652HDLG1328为G1955G4581CHD的重要G17896G5464G1055一。胆固醇酯转移蛋白G708CHOLESTERYLESTERTRANSFERPROTEIN，CETPG709抑制剂G2029能有G6940G3332G2331G20652HDL，因而CETP抑制剂G5062成为治疗CHD的一个潜在靶标。G11458前抑制CETPG1039要有G1016G12193G17896G5464一是G17902G17819G8892G4568G11135G14507，G1363G7438G1319产生G19036对CETP的G14270G17535G6251G1319；G1120是G17902G17819G7393G11004CETP抑制剂，G17810G2052抑制CETP的G11458的。G11458前，G19555G11540研究的G9157G1849，G17246来G17246G3822G13479G7512的CETP抑制剂G2656G6251CETPG11135G14507G15999发G10628G2656G5332发。1抗胆固醇酯转移蛋白疫苗CETI1CETI1是一G12193G8892G4568G11004的G13969G12879G6251胆固醇酯转移蛋白G11135G14507G32821，G17902G17819G11135G14507G8892G4568产生G6251G1319抑制CETP的有G6940性在G20652G14038G1832G17535G990G5483G2052G1114G20576G16789，G4439能G7138G7186G2331G20652HDLC2。G17837G12193方G8873也在G1166G1319内进行G1114G16809G20576，IG7411临床G16809G20576中，36G2529G2475G16809G13785G2010G2047G8892G4568G1114250MG的CETI1，G13479G7536G1363G6251CETPG6251G1319G2331G20652；在一G2004523G2529G2475G16809G13785的进一G8505临床G16809G20576中，8G2529G6521G2475G1114G125442G8437G8892G4568，G13479G7536G6251CETPG6251G1319进一G8505G990G2331，G1000G13796G2475性G3921，G8821有G7138G7186的G5334G5132G2465G5224，IG7411临床研究G7186G12046，G7424G2709能剂G18339G1393G17194性G3332G6564G20652G6251G1319G6940G1227。G11458前AVANTIMMUNOTHERAPEUTICSG1856G2508G8503在进行G13969G12879G6251胆固醇酯转移蛋白G11135G14507CETI1G11004于治疗HDLCG1314G991的G44G44G7411临床研究3,4，G7100在G16792G1227CETI1的G4445全性、G1825G11135G2419性G2656G18339G6940关G13007。G8503在G5332发此G12879CETP抑制G11135G14507的G17836有G17757G10802G1856G2508的CP529414，G10628G3800于IIG7411临床研究中，PHARMACIAG1856G2508的SC795尚G3800于临床前研究。H3CLEUOARGLYSLEUARGLYSARGLEULEUARGNH2A131CETI1A15A14A16A17A18A19FIG1THEAMINOACIDSEQUENCEOFCETI12单克隆抗体、天然产物及提取物作为CETP抑制剂SWENSON等5G11004单克隆G6251G1319MAB特G5334性G3332抑制CETP，G12544一G8437向G1166G12879G7186G12046抑制CETP可G1363HDLCG2331G20652，LDLCG19489G1314。3从天然产物中也G2010离G5483G2052一些CETP抑制剂，如胆固醇衍生物、G14038肪酸G12879、海洋产物G2462细菌G2656真菌的发酵产物等。如DAVIDBRUCKNER等6从青霉菌中G5483G20524G12193衍生物14G32822，G4439们都具有CETP抑制G1328G11004，其抑制活性IC50G2010G2047为1、02、0015、0030M。LEE,JULIEC等7发G10628真菌内的G6564取物5G32822也能抑制CETP，其G1319外抑制活性IC50为40M。OOOOHOO1OOOOOOOH2OOOOOOOHCL3OOOOOOOHCL4NOHOHOHOHOOOHH5A202A21A22A23A24A25A26A27A28A23A29A30A26A31A32A33FIG2THESTRUCTURESOFPENICILLIDEDERIVATIVESANDEXTRACTFROMFUNGUS3进入临床研究阶段的化学合成的小分子CETP抑制剂431JTT705CETP抑制剂JTT705ROCHE/JAPANTOBACCOG32823是G1166工合成的小G2010子化学制剂，G10628G3800于IIG7411临床研究中8。G4439G17902G17819与CETP形成G1120硫G19202，G2331G20652G1114HDLC，G19489G1314G1114非HDLC，抑制G1114CETP的活性。在G20652胆固醇G1832G1319内，JTT705可G1363HDLCG8712G5191G2331G20652近2倍，非HDLCG19489G1314509。在IG7411G16809G20576中，与对照组相G8616，连续14天每天G7393G11004600MG或900MGJTT705的G2475G16809G13785，其HDLCG2331G20652G11144045，LDLCG19489G1314G1114152010。JTT705的G13796G2475性良G3921，G8821有引起严重的毒性G2465G5224。另一G20045研究将普伐他汀G12879药物与JTT705合G11004，联合G11004药G13796G2475性也良G3921，也G8821有产生G7138G7186的不良G2465G522411。在IIG7411临床研究中，198个具有中等程G5242G20652G14038血症的患G13785G2010G2047G6521G24753G12193剂G18339JTT705治疗4周，G20652剂G18339组导致HDLG2331G2065237，并G1363LDL胆固醇G8712G5191G19489G1314712。32TORCETRAPIDCETP抑制剂托切普TORCETRAPID,PFIZERG32823是另一新型的CETP抑制剂，相较而言，TORCETRAPID的G1328G11004G7368G3921，是G8616JTT705G7368有G6940的CETP抑制剂13。近G7411的一G20045TORCETRAPID单盲、G4445慰剂对照G16809G20576报道，19G2529HDL1034MMOLL1成G1166G7393G11004G4445慰剂4周后，G19555G7438G2010组为TORCETRAPID组G708日G7393120MG，单独G7393G11004或与阿托伐他汀20MGD1合G110044周G709G2656G4445慰剂组。G13479G7536发G10628单独G7393G11004TORCETRAPIDG13785CETP活性G5191均G19489G131428，HDLCG8712G5191G2331G2065246；与阿托伐他汀合G11004，CETP活性G19489G131438，HDLCG8712G5191G2331G2065261。当药G18339加倍后，CETP活性进一G8505G19489G1314G708G5191均65G709、HDLCG2331G20652超G1781910014。因联合G11004药G4445全G13796G2475性G3921，故在TORCETRAPID与其他他汀G12879药物连G11004方面进行G1114大规模的G16809G20576，以G7411能够找G2052G7368G3921治疗冠心病的方G887315。TORCETRAPID经历G1114全球性大规模的三G7411G4466G20576，从G5483G2052的数据看，G4439对G19489G1314冠脉疾病发生风G19517是有G6940的，但也带来G1114严重的不良G2465G5224头痛、血压G990G2331G2462心血管毒性16，G1363其致死率G20652于对照组，G11458前TORCETRAPIDG16809G20576G15999迫停止17。5SONHOJTT705NF3COONOOF3CCF3TORCETRAPIDA343A35A36A37JTT705A38A39A40A41TORCETRAPIBA42A43A44FIG3THESTRUCTURESOFCETPINHIBITORSJTT705ANDTORCETRAPIB4化学合成的小分子CETP抑制剂近年来大G18339文献报道G1114小G2010子CETP抑制剂，G7424文对具有代表性的小G2010子CETP抑制剂按照G13479G7512G12879型进行阐述。41含硫化合物CETP的G3822G13969链中含有7个半胱氨酸18，至G4581存在一个游离的半胱氨酸巯基。基于G17902G17819形成G1120硫G19202，修饰CETPG2010子中游离的巯基，G11458前G5062合成G1114一G13007列的具有CETP抑制活性的硫酯、G1120硫化物G2656硫醚，如硫酯6，G1120硫化物7G2656硫醚8G32824，其CETP抑制活性IC50G2010G2047为2、12G265619M19。G1120硫化物的抑制活性G7138G7186G20652于硫醚G12879化合物，G2419因可能为硫醚中G8821有可以释放的巯基与CETP中游离的巯基形成G1120硫G19202；而硫酯G12879化合物与G1120硫化物的抑制活性G2029相当。NHOCLCLSO6NHF2CH3CO2CSCF3SNCO2CH3CF2HCF37NHF2CH3CO2CSCF3NCO2CH3CF2HCF38A454A46A47A48A49A50A51A52FIG4THESTRUCTURESOFCOMPOUNDINCLUDINGSULFUR642吡啶G12879BAYERG1856G2508采G11004G20652G17902G18339G12591G17885，发G10628G3822取代的吡啶对CETP有抑制G1328G1100420。如G3822取代吡啶化合物9、10G32825，其CETP抑制活性IC50G2010G2047为6M、9NM。对9进行G13479G7512修饰，在G2010子中引G1849一个G6175性中心，并对吡啶G1403链进行取代G548310，其抑制活性G3698加G11141000倍。然而，G16825G12879化合物代G16886不G12295G4462，G19668进一G8505对其进行G13479G7512G6925造。NCH2OHF3CFN9NFF3CFOH10A535A54A55A56A57A58A59A60A61A62A63FIG5THESTRUCTURESOFSUBSTITUTEDPYRIDINEDERIVATIVES43G3247G8694G2957G2845G2656G3247G8694G14828G12879将吡啶G12879抑制剂G2010子G1403链的G1283醇引G1849G2052G10627中，G5483G2052G2030性的吡啶G12276G10627化合物5,6,7,8G3247G8694G2957G2845，其G13479G7512G8616吡啶G12879小G2010子抑制剂G12295G4462。如化合物11G265612G32826，其CETP抑制活性IC50G2010G2047为12NMG26569NM，G1000化合物12G1328为G1517G17885化合物G5062进G1849临床前研究G19466G858521。G2045G11004生物G11017子等G6502G2419G2029，G1260化G3247G8694G2957G2845G12879抑制剂G5483G2052G1114G8706G2419子的等G6502G12879G1296物G3247G8694G14828G12879化合物，如化合物13G265614G32826，其G1319外抑制活性IC50G1552均为3NM，化合物14并G1328为BAYERG1856G2508的G12544G1120代G1517G17885化合物G5062进G1849临床前研究G19466G858522。7NIPRFF3CFOH11NFOHFFFF12FOHFFFF13FOHFFFF14A646A65A66A67A68A69A65A66A70A71A72A73A74A75A76FIG6THESTRUCTURESOFTETRAHYDROQUINOLINEANDTETRAHYDRONAPHTHALENEDERIVATIVES441,1,1三G86913氨基2G1005醇G12879SEARLEG1856G2508G12591G17885组合化学G5223，发G10628N,NG1120取代三G86913氨基2G1005醇G12879G1296物具有CETP抑制活性，并以此为G1820导物对其进行G13479G7512修饰G5483G2052化合物15、16G32827，G4439们的CETP抑制活性IC50G2010G2047为003M、0003M，G7186G12046G1114较G3921的抑制G1328G1100423。OCF2CF2HNF3COHO15ONOHF3CCF2CF2HO16CLA7771,1,1A78A793A80A812A82A83A84A85A86A87A88A89FIG7THESTRUCTURESOF1,1,1TRIFLUORO3AMINO2PROPANOLDERIVATIVES8在3PHO的G14531G10627G990引G1849小的G1158G14038性G9931基、G2360G9931基、G2360代G9931氧基有G2173于G6564G20652抑制CETP的转G17828能G2159。G11458前，化合物16是G16825G12879抑制剂中活性G7380G5390的，不足的是，由于G2487G7393生物G2045G11004G5242G5058G2656与血浆蛋白的非特G5334性G13479合，导致其G1319内药G6940G19489G1314，因此G17836有G5465进一G8505G1260化。45三G2789G2656G3247G2789G12879PARKEDAVIS发G10628PD14019517G32828能G17885G6333性抑制CETP的活性，其CETP抑制活性IC50为30M；SIKORSKI发G10628G1114一G13007列的三G2789硫醇G12879衍生物具有CETP抑制活性，如化合物18G32828，其IC50为50M24，G17837G1016G12193化合物其活性都较G5058。在此基G11796G990进行G13479G7512G6925造合成G1114G3247G2789G12879化合物，如化合物19G32828，其CETP抑制活性IC50为230NM25，抑制G1328G11004与三G2789G12879化合物相G8616，活性有较大程G5242的G6564G20652。NNNSH17ONNNH3CH2C12HS18NNF3COONNNNCF3F3C19A908A91A92A93A94A92A95A96A97A98A99A100FIG8THESTRUCTURESOFTRIZOLEANDTETRAZOLEDERIVATIVES46其他G12879HARIKRISHNAN等26G6563述G1114一G13007列的2G14471基G14531并G5706G2789G12879衍生物，如化合物20G32829，具有CETP抑制活性，其IC50G1552为280NM。日G7424TOBACCOG1856G2508于2004年报道G1114一G12193新G13479G7512G12879型的CETP抑制剂N,NG1120G14488基氨基G3247G8706G2789G12879化合物27，如化合物21G32829，G16825G12879化合物可以看G1328是TORCETRAPIB的G5332G10627G12879G1296物，其IC50均小于1M。另外，一些含G7446G10627的G14030G12879化合物G2528样具有CETP抑制活性，如化合物22G32829，其IC50G1552为409NM28。9NONHOO20F3CNNCF3CF3NNNNOHO21CLCLNOMEMEETCL22A1019A102A103A104A105A106A107A108A109A110A111A112FIG9THESTRUCTURESOFREPRESENTATIVECOMPOUNDS综G990G6164述，CETP抑制剂的研究G5062经取G5483重大进展，研究G5617G17347G2656G1328G11004靶G9869也G5062G7138G11842，但临床治疗方面G1185G7422取G5483重大G12373G11784。G15441然G11458前G5062合成G1114大G18339的具有CETP抑制G1328G11004的化合物，但要进G1849临床的G19466G8585G17329离G17836很G17840。小G2010子CETP抑制剂是潜在的有G6940治疗心血管疾病的新型药物，然而，TORCETRAPIBIIIG7411临床的G3845G17145G20056G12046G11540G4559找G4445全、有G6940的CETP抑制剂G1185面临G11540G16780G3822G6373G6124。REFERENCES1BELAFA,ERNSTJSHDLINATHEROSCLEROSISACTORORBYSTANDERJATHEROSCLEROSISSUPPLEMENTS,2003,421292RITTERSHAUSCW,MILLERDP,THOMASLJ,ETALVACCINEINDUCEDANTIBODIESINHIBITCETPACTIVITYINVIVOANDREDUCEAORTICLESIONSINARABBITMODELOFATHEROSCLEROSISJARTERIOSCLERTHROMBVASCBIOL,2000,2021061123DAVIDSONMH,MAKIK,UMPOROWICZD,ETALTHESAFETYANDIMMUNOGENICITYOFACETPVACCINEINHEALTHYADULTSJATHEROSCLEROSIS,2003,16911131204KOMORITCETI1AVANTCURROPININVESTDRUGS,2004,53334338105XIONGXQ,ZHAODM,CHENGMSPROGRESSINTHESTUDYOFTHECHOLESTERYLESTERTRANSFERPROTEININHIBITORSJSHENYANGYAOKEDAXUEXUEBAO（G8796G19463药G12197大学学报）2004,2143143206DAVIDB,FRANKTH,VOLKHARTL,ETALDIBENZODIOXOCINONESANEWCLASSOFCETPINHIBITORSJBIOORGANICMEDICINALCHEMISTRYLETTERS,2005EEJC,COVALSJ,CLARDYJACHOLESTERYLESTERTRANSFERPROTEININHIBITORFROMANINSECTASSOCDFUNGUSJJOURNALOFANTIBIOTICS,1996,4976936968GROOTHGJ,KUIVENHOVENJA,STALENHOEFAF,ETALEFFICACYANDSAFETYOFANOVELCHOLESTERYLESTERTRANSFERPROTEININHIBITOR,JTT705,INHUMANSARANDOMIZEDPHASEA113DOSERESPONSESTUDYJCIRCULATION,2002,105215921659OKAMOTOH,YONEMORIF,WAKITANIK,ETALACHOLESTERYLESTERTRANSFERPROTEININHIBITORATTENUATESATHEROSCLEROSISINRABBITSJNATURE,2000,40620320710HIROSHIO,FUMIHIKOY,KOREKIYOW,ETALACHOLESTERYLESTERTRANSFERPROTEININHIBITORATTENUATESATHEROSCLEROSISINRABBITSJNATURE,2000,40620320611SCHAEFER,EJ,ASZTALOS,BFCHOLESTERYLESTERTRANSFERPROTEININHIBITION,HIGHDENSITYLIPOPROTEINMETABOLISMANDHEARTDISEASERISKREDUCTIONJCURRENTOPINIONINLIPIDOLOGY,2006ONALDWCRAISINGHIGHDENSITYLIPOPROTEINWITHCHOLESTERYLESTERTRANSFERPROTEININHIBITORSJCURRENTOPINIONINPHARMACOLOGY,2006,616216813BROUSSCAUME,SCHAEFEREJ,WOLFEML,ETALEFFECTSOFANINHIBITOROFCHOLESTERYLESTERTRANSFERPROTEINONHDLCHOLESTEROLJNENGLJMED,2004,350150551514BROUSSEAUME,SCHAEFEREJ,WOLFEML,ETALEFFECTSOFANINHIBITOROFCHOLESTERYLESTERTRANSFERPROTEINONHDLCHOLESTEROLJNENGLJMED,2004,350151505151515ZAREBA,GRAZYNATORCETRAPIBANDATORVASTATINANOVELCOMBINATIONTHERAPYFORDYSLIPIDEMIAJDRUGSOFTODAY,2006,4229510216TOTH,PPTORCETRAPIBANDATHEROSCLEROSISWHATHAPPENEDANDWHEREDOWEGOFROMHEREJFUTURELIPIDOLOGY,2007,2327728417SUCKLING,KEITHTHECONTINUINGCOMPLEXITIESOFHIGHDENSITYLIPOPROTEINMETABOLISMINDRUGDISCOVERYANDDEVELOPMENTJEXPERTOPINIONONTHERAPEUTICTARGETS,2007,1191133113618DRAYNAD,JARNAGINAS,MCLEJ,ETALCLONINGANDSEQUENCINGOFHUMANCHOLESTEROLESTERTRANSFERPROTEINCDNAJNATURE,1987,327612363263419KIMIYAM,HIROSHIO,HISASHISS2ACYLAMINOPHENYL2,2DIMETHYLPROPANETHIOATESASCETPINHIBITORSJBIOORGANICMEDICINALCHEMISTRYLETTERS,2004,142589259120MAEDAK,NAGAMORIH,NAKAMURAH,ETALPREPARATIONOFNPHENYLORNHETEROCYCLYLDIBENZYLAMINECOMPOUNDSASINHIBITORSOFCHOLESTEROLESTERTRANSPROTEINCETPANDMEDICINALUSETHEREOFWO,04020393P20040311