(药物化学)

1Medicinalchemistry(药物化学)isadisciplineofchemistrythatconcernsitselfwiththediscovery,designanddevelopmentoftherapeuticchemicalsforthetreatmentofhumanandanimaldisease.MedicinalChemistryIUPACdefinition:Medicinalchemistryisachemistry-baseddiscipline,involvingaspectsofbiological,medicalandpharmaceuticalsciences.Itisconcernedwiththeinvention,discovery,design,identificationandpreparationofbiologicallyactivecompounds,thestudyoftheirmetabolism,theinterpretationoftheirmodeofactionatthemolecularlevelandtheconstructionofstructure-activityrelationships(SAR),therelationshipsbetweenchemicalstructureandpharmacologicalactivitiesforaseriesofcompounds.2Prof.JohnReiner(Left)taughtundergraduatemedicinalchemistryatTianjinUniversityfrom2004to2006.HeleftChinainthesummerof2006toreturnbacktoworkintheUS(phototakenonJuly7,2006).3Prof.PaulGroundwater(formerlyUniversityofSunderland,UK)spentaboutaweekteachingundergraduatemedicinalchemistryatTianjinUniversityin2007andalsoin2008.HeiscurrentlyprofessorofmedicinalchemistryattheUniversityofSydneyinAustralia.4DrAndrewD.WestwellSeniorLecturerinMedicinalChemistryWelshSchoolofPharmacyCardiffUniversity,UK.From2to9May2009,Andy(inthemiddle)gave10lecturestotheundergraduatestudents(year2006class)5Keypoints:1.Medicinalchemistryisadisciplineofchemistry.2.Medicinalchemistrydealswiththerapeuticchemicals.6Indigo靛蓝NHHNOO7OSNHNHNO2NNHNNNSNNMeMeOOOHNH2NOHONSHNNH2OHOOCO2HHHOOGlaxo'sRanitidine(Zantac)雷尼替丁Pfizer'sSildenafil(Viagra)西地那非ICI'sAtenolol(Tenormin)阿替洛尔SmithKlineBeecham'sAmoxicillin阿莫西林8西药Drug(Medicine)Smallmoleculedrugs(syntheticchemicals)Biologics(biologicalmacromolecules)中药(中成药)HerbalMedicine[ComplementaryMedicineAlternativeMedicine]假药FakeDrug毒品Streetorclubdrugs保健食品DietarySupplements安慰剂Placebo9Thedefinitionofadrug(medicine)isthatitshouldbeatherapeuticchemical,notonlyabiologicallyactivechemical.Adrugmustmeetthecriteriafortherapeuticeffectsandsideeffects(ithastobeproventobesafeandeffective).Theapprovalofadrugformarketingdependsontheparticularrequirementofeachcountry.Therearedrugsthatwereapprovedinsomecountries,butnotinothers.10ADrugorAPoison???‘TheDoseMakesthePoison’FatherofModernToxicologyFatherofModernToxicologyPARACELSUS((TheophrastusPhilippusAureolusBombastusvonHohenheim)14931493--15411541‘Wasistdasnitgifftist?alledingsindgift/undnichtsohngifft/Alleindiedosismachtdaseindingkeingiftist.’Whatisnotpoison?Allthingsarepoisonandnothing[is]withoutpoison.Onlythedosemakesathingnottobepoison.11Toxicityandthedosage‹LD50:thelethaldoserequiredtokill50%ofagroupofanimals.‹ED50:thedoserequiredtoproducethedesiredeffectin50%oftheanimals.Comparisonoftherapeuticandlethaldosecurves12ASelectionofNaturalCarcinogensaniseapplesbananasbrocollibrusselsproutscabbagecarrotscauliflowercelerycinnamonclovescocoacomfreyteafennelgrapefruitjuicehoneydewmelonhorseradishkalemushroomsmustardorangejuiceparselyparsnipspeachesblackpepperpineapplesradishesraspberriestarragonturnips13ExamplesofoverdoseMetabolicSaturation!!!MetabolicSaturation!!!14ProblemswithparacetamoloverdoseParacetamolAcetaminophen扑热息痛对乙酰氨基酚Paracetamolhasbeenwidelyusedasananalgesicandanitpyretic,butitisnowthemostcommondruginself-poisoningwithahighrateofmorbidityandmortality.15TheSynthesisofParacetamolOHdiluteHNO3OHOHNO2NO2ortho,36%para,25%OHNO2H2,Pd-CHOAcOHNH2Ac2OParaacetylaminophenolParacetamol+HOHNO16TheMetabolismofParacetamolHO2CNHHNCO2HNH2OSHOGlutathioneTheprimarypathwaysforparacetamolmetabolismareglucuronidationandsulfationtonontoxicmetabolites.Approximately5%ofatherapeuticdoseismetabolizedbycytochromeP4502E1totheelectrophileN-acetyl-p-benzoquinoneimine(NAPQI).NAPQIisextremelytoxictotheliver.Ordinarily,NAPQIisrapidlydetoxifiedbyinteractionwithglutathionetoformcysteineandmercapturicacidconjugates.Ifglutathioneisdepleted,NAPQIinteractswithvariousmacromolecules,leadingtohepatocyteinjuryanddeath17Fortheauthoritywhenapprovingadrug:Abalancehastobestruckbetweenadrug’stherapeuticbenefitanditstoxicity.Forthepatientwhenusingadrug:Thedrugisusedwhereitspotentialbenefitstothepatientoutweighitspotentialrisks,whichisajudgementthathastobemadebythemedicalprofessionalandthepatientconcerned.Thebenefitsoutweightherisks18Medicines:Prescription-only-medicine(Rx)Over-the-countermedicine(OTC).Medicinehasaspecialstatus,whichmeansthatitsmarketingisstrictlyregulated.Direct-to-consumeradvertisingofprescription-onlymedicine(Rx)iscurrentlyonlypermittedintheUSandNewZealand.19TheRegulatoryAuthorities:China:国家食品药品监督管理局StateFoodandDrugAdministration(SFDA)USA:TheFoodandDrugAdministration(FDA)EU:TheEuropeanMedicinesEvaluationAgency(EMEA)Japan:TheMinistryofHealth,LabourandWelfare(MHLW)UK:TheMedicinesandHealthcareproductsRegulatoryAgency(MHRA)20OHCH3CH3OBrandname:LivialGenericname:Tibolone2122AboutFDA23ABriefHistoryofFDATheFDAbeganastheDivisionofChemistryandthen(afterJuly1901)theBureauofChemistryintheDepartmentofAgriculture.ThemoderneraoftheFDAdatesto1906withthepassageofthePureFoodandDrugAct;thisaddedregulatoryfunctionstotheagency’sscientificmission.TheBureauofChemistry’snamechangedtotheFood,Drug,andIns