代表讲稿2-Doripenem-ANewBroa.ppt

Doripenem ANewBroad SpectrumCarbapenemAntibiotic GroupMember0440213044021604415150441523 SARofdoripenem FromPenicillinsToCarbapenems 从青霉素到碳青霉烯 沙纳霉素 硫霉素 Thienamycin 的发现 CarbapenembeforeDoripenem StructureofDoripenem 1R 5S 6S 2 3S 5S 5 substitutedpyrrolidin 3 ylthio 6 1R 1 hydroxyethyl 1 methylcarbapen 2 em 3 carboxylicacids AnalysisofSAR MechanismStabilityb lactamasestabilitystabilityagainsthumanrenaldehydropeptidaseI DHPI AntimicrobialfeaturesToxiceffects Mechanism Likeallbeta lactamantimicrobialagents carbapenemsactbyinhibitingbacterialcellwallsynthesisbybindingtoandinactivatingpenicillin bindingproteins PBPs b lactamasestability doripenemhasatrans configured6 hydroxyethylgroup whichprotectsitagainstbeta lactamases ResistancetocarbapenemsdevelopswhenbacteriaacquireordevelopstructuralchangeswithintheirPBPs whentheyacquiremetallo beta lactamasesthatarecapableofrapidlydegradingcarbapenems orwhenchangesinmembranepermeabilityariseasaresultoflossofspecificoutermembraneporins B 内酰胺环与二氢吡咯环反式拼合对B 内酰胺酶高度稳定 顺式则易被酶水解 6 位引入立体因素较大的反式a 羟乙基侧链 降低了钝化酶对结构的适应性 保护B 内酰胺环不被B 内酰胺酶进攻 Humanrenaldehydropeptidase1 DHP1 stability 1 beta methylsidechainprovidesresistancetotherenalenzymeDHP1 AntimicrobialFeatures I 由于B 内酰胺环的张力较大 其中羰基氮原子上的孤对电子不能完全共轭 易受亲核进攻 且1位用亚甲基取代了硫原子 亚甲基sp3杂化的键角小于硫醚的键角 并由于C2与C3间双键的存在 使二氢吡咯趋于平面结构 活化了B 内酰胺环的反应活性 这是碳青霉烯类抗生素抗菌活性强的的化学基础II 2位具有碱性烷基硫醚基团 使其更易进入G 杆菌的细胞外膜 III C 3羧基使碱性下降 且是亲水基团可扩大抗菌谱 提高对G 的抑制作用和与蛋白的亲和力 Aparticularfeature thesidechainatposition2 sulfamoylaminomethylgroup ToxicEffects Doripenemdisplaysfavorablepharmacokinetic pharmacodynamicandtoxicologicalfeatures similartothoseofmeropenem Doripenemhasnoconvulsiveactivity DoripenemdidnotcauseanyinhibitionmuscimolbindingtotheGABAreceptor So itsneurotoxicitymaybenegligibleinclinicaluse Synthesisofdoripenem 1R 5S 6S 6 1R 1 羟乙基 2 3S 5S 5 氨磺酰胺基甲基吡咯烷 3 基 巯基 1 甲基 1 碳代 2 青霉烯 3 羧酸 4R 5S 6S 6 1R 1 hydroxyethyl 4 methyl 7 oxo 3 3S 5S 5 sulfamoylaminomethyl pyrrolidin 3 yl thio 1 azabicyclo 3 2 0 hept 2 ene 2 carboxylicacidmonohydrate Doripenemwassynthesizedbythecondensationof 2S 4S 1 t butoxycarbonyl 2 N t butoxycarbonyl sulfamoylamido methyl 4 mercaptopyrrolidone 7 and 1R 5S 6S 6 1R 1 hydroxyethyl 2 diphenoxyphosphonyloxy 1 methyl 1 carba 2 penem 3 carboxylicacidp nitrobenzylester 8 followedbydeprotectionwithayieldof50 5 Compound7wasobtainedfromtrans 4 hydroxy L prolinebyesterification protection reduction SN2substitution Mitsunobureactionandalcoholysiswithayieldof50 8 Theoverallyieldwasabout26 basedontrans 4 hydroxy L proline 反式 4 羟基 L 脯氨酸经酯化 保护 还原 SN2取代 Mitsunobu反应 醇解得到 2S 4S 1 叔丁氧羰基氨磺酰胺基 甲基 4 巯基吡咯烷 7 收率50 8 7与 1R 5S 6S 6 1R 1 羟乙基 2 二苯氧磷酰氧基 1 甲基 1 碳代 2 青霉烯 3 羧酸对硝基苄酯 8 缩合 脱保护 得到多尼培南 收率50 5 以7计 总收率接近26 以反式 4 羟基 L 脯氨酸计 Step1Step2Step3Step4Step5Step6NEXT Step1 Boc 叔丁氧羰基 保护氨基 Ms 甲磺酰基 活化羟基 Step2 酯基还原 还原剂的选择SN2反应 4位发生构型反转 Step3 Boc NHSO2NH2 N 叔丁氧羰基氨磺酰胺MitsunobuReaction醇解脱去乙酰基 Step4 化合物8 1R 5S 6S 6 1R 1 羟乙基 2 二苯氧磷酰氧基 1 甲基 1 碳代 2 青霉烯 3 羧酸对硝基苄酯 MAP 市售 缩合反应 Step5 脱掉 Boc保护基 Step6 脱掉 PNB 对硝基苄基 氢解反应 MitsunobuReaction Researchisadifficultjobforustochallenge Fighting Comparisonofdoripenemandothercarbapenems Comparisonofdoripenemandothercarbapenemsonpharmacology Antibacterialmechanismsarethesamewithotherbeta lactamantibiotics combiningwithbacterialpenicillin bindingprotein PBPs inhibitesbacterialcellwallsynthesis Doripenemhasstrongantibacterialactivityandstabilityagainstthevastmajorityofbeta lactamaseandkidneydehydrogenationendopeptidase DHP 1 1 AntibacterialactivityagainstG Methicillin susceptiblestaphylococcusaureus Staphylococcusepidermidis slightlylowerthanimipenem strongerthanmeropenemandbiapenemMethicillin resistantStaphylococcusaureus Staphylococcusepidermidis 2 4timesstrongerthanothercontroldrugsStrongestantibacterialactivitytoStreptococcuspyogenes Penicillin susceptibleStreptococcuspneumoniae similartoimipenem strongerthanmeropenemandbiapenemPenicillin resistantStreptococcuspneumoniae identicalwithothersEnterococcusfaecalis slightlylowerthanimipenem strongincontrasttootherdrugs ComparisonoftheMIC90 g ml fordoripenemandthreeothercarbapenemstestedagainstGram positivepathogens Strains NO DoripenemImipenemMeropenemBiapenem Methicillin susceptiblestaphylococcusaureus 30 0 0630 0320 1250 125 Methicillin resistantStaphylococcusaureus 30 16323264 Methicillin susceptibleStaphylococcusepidermidis 46 0 0630 0160 1250 125 Methicillin resistantStaphylococcusepidermidis 27 3212864128 Streptococcuspyogenes 42 0 0040 0080 0080 008 Penicillin susceptibleStreptococcuspneumoniae 25 0 0080 0080 0160 016 Penicillin resistantStreptococcuspneumoniae 25 0 50 250 50 5 Enterococcusfaecalis 26 4188 MIC90 MICatwhich90 ofthestrainswereinhibited 2 AntibacterialactivityagainstG DoripenemissensitivetomanyG bacteria suchas E coliKlebsiellapneumoniae 肺炎克雷白杆菌 Enterobacteriaceae 肠杆菌 Proteusmirabilis 奇异变形杆菌 Proteusvulgaris 普通变形杆菌 Haemophilusinfluenza 流感嗜血杆菌 P aeruginosa 铜绿假单胞菌 ComparisonoftheMIC90 g ml fordoripenemandthreeothercarbapenemstestedagainstGram negativepathogens Strains NO DoripenemImipenemMeropenemBiapenem E Coli 30 0 0320 1250 0160 063Klebsiellapneumoniae 30 0 0630 250 0320 125Aerobactercloacae 30 0 0630 50 0630 125P aeruginosa 83 2824Proteusmirabilis 27 0 540 1252Proteusvulgaris 30 0 540 1254Haemophilusinfluenza 50 0 540 254MIC90 MICatwhich90 ofthestrainswereinhibited 3 AntibacterialactivityagainstP aeruginosa Pseudomonas aGram negativebacterium isoneoftheleadingcausesofresistanthospital acquiredinfectionsand becauseofincreasingmulti drugresistance treatmentoptionsarelimited DoripenemappearstohavemorepotentinvitroactivityagainstP aeruginosathanmeropenem Presenceofcarbapenem resistantmutantswithinzonesofgrowthinhibitionofP aeruginosaaroundcup DoripenemcouldpreventgrowthofthemutantsofP aeruginosaataconcentrationthatwouldinhibitcellgrowth 4 Pharmacokinetics parenteralinjectionantibioticsthemainmetabolites thebeta lactamringhydrolysisuntiedproducttheproductmainlybyglomerulusfiltration90 ofurineexcretion Conclusion Doripenemisapromisingnewcarbapenemwithsimilaranti G activitytothoseofimipenemandanti G activitytothoseofmeropenemDoripenemhadslightlygreateractivityagainstPseudomonasaeruginosa Marketprospects Marketprospects Idealantibiotics safe efficient broad spectrum Thesituationforantibioticsis astheyusedinthelargeclinicalapplication resistantofbacteriahasbecomeincreasingserious Marketprospects Overcomebacterialresistancefromthreeaspects 1 preventtheabuseofantibiotics 2 developnewantibiotics 3 Searchtheinhibitorsofbacterialenzymeforhydrolysisofantibiotics Marketprospects DoripenemwasfirstlaunchedinJapaninSep 2005 ItscommercialnameisFinibax Theinjectionhadbeenlicensedforthetreatmentofcomplicatedintra abdominalandcomplicatedurinarytractinfections Thenosocomialpneumoniaindicationfordoripenemhadbeengranted fast track statusbytheFDAinDec2006 DevelopingProcess Shionogi Co Ltd Osaka Japan Finibax0 25gIVSolution launchedinJapanin2005 licensedtoPeninsulaPharmaceuticalsInc Alameda CA USA asubsidiaryofJohnson Johnson in2005 Doripenemhasreceivedfast trackdesignationfromtheU S FDAforthetreatmentofnosocomialpneumonia includingventilator associatedpneumonia InphaseIIItrialsfortreatmentofcomplicatedintra abdominalinfectionandcomplicatedlowerurinarytractinfectionsin2006 12 Marketprospects Inclinicaltrials doripenemwaswell tolerated Themostadverseeventsseenwerediarrhea nausea constipation urinarytractinfectionanddecubitusulcer commonlyknownasabedsore Marketprospects Thecurrentglobalsituationofanti infectivemarket anti infectivedrugmarketsalesaccountforabout15 oftotalsales thatis thesecondoftheglobalpharmaceuticalmarket Amongthem antibioticsmakethelargestshare about8billiondollars Thecarbapenemantibioticsis1billionannually Nowcarbapeneminthedrugmarketshareisrising thedemandforcarbapeneminmarkethadincreasedby50 lastyear Thuscarbapenemdrughasbeenthehotdevelopmentofantibiotics Marketprospects However thepotentialexistsforsomemetallo blactamasesthatcandestroycarbapenemcompoundstobemoredisseminated prudentprescibingpracticeshouldscreenmultidrug resistantisolatesforthismechanism Onlywiththiseffortwilldoripenembeabletomaintainitswidespectrumofactivityandpotentialclinicalutility Marketprospects References 4 ShihomiSakyo HaruyoshiTomita KoichiTanimoto ShuheiFujimoto YasuyoshiIke PotencyofCarbapenemsforthePreventionofCarbapenem ResistantMutantsofPseudomonasaeruginosa J Antibiot 59 4 220 228 2006 5 MasahitoHoriuchi MegumiKimura MiwaTokumura NobuyoshiHasebe TohkoArai KohjiAbeAbsenceofconvulsiveliabilityofdoripenem anewcarbapenemantibiotic incomparisonwith lactamantibiotics 1 RonaldN Jones 1 2 HollyK Huynh 1andDouglasJ Biedenbach1ActivitiesofDoripenem S 4661 againstDrug ResistantClinicalPathogens 2 ShazadMushtaq 1YigongGe 2andDavidM Livermo