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1、REVIEWSCasehisToryAliskiren:thefirstrenininhibitorforclinicaltreatmentChrisJensen,PeterHeroldandHansRudolfBrunnerAbstract
2、Thefirstevidenceoftheexistenceofreninwaspresentedover100yearsago.However,theimportanceofreninandtherenin–angiotensinsysteminthepathogenesisofcardiovas
3、culardiseasewasonlyfullyrealizedinthe1970s.Itwasanother20yearsbeforethefirstinhibitorsofreninwereavailableforclinicalresearch.Here,wedescribethediscoveryanddevelopmentofaliskiren,anorallyactiverenininhibitor,whichbecamethefirstdruginitsclasstoreceiveregulatoryapproval.In2
4、007,itwasapprovedforthetreatmentofhypertensionbytheUSFoodandDrugAdministrationandtheEuropeanMedicinesAgency.Aliskirenalmostneverwas.FollowingthemergerofTherenin–angiotensinsystemindiseaseHypertrophyCiba–GeigywithSandoztoformNovartisin1996,TheRAScascadestartswithangiotensi
5、nogen,aproteinAnincreaseinventricularmass,whichistypicallycharacterizedandthelaunchoftheantihypertensivedrugvalsartanthatissecretedbytheliver(FIG. 2).Fromthissubstrate,thebyanincreasedcardiac(Diovan;Novartis)in1997,thefateoftheinvestiga-decapeptideangiotensinIisthencleave
6、dbytheenzymemyocytesizeinconjunctiontionalrenininhibitoraliskirenseemedtobeaforgottenrenin,whichisproducedinthekidney(theactivityofwithcardiacfibrosis.backshelfofaresearchlaboratory.However,asmallreninintheplasmaisreferredtoasplasmareninactivityFibrosisgroupofformerCiba–G
7、eigyemployeesconvincedthe(PRA)).AngiotensinIisthenfurthertransformedbytheTheformationofexcessnewmanagementofNovartistoout-licensealiskirentoangiotensin-convertingenzyme(ACE)toproducetheconnectivetissue.Speedel,astart-upbiopharmaceuticalcompanyestab-octapeptideangiotensinI
8、I,whichbindstoangiotensinlishedin1999,tokeepaliskireninclinicaldevelopmentIIsubtype1receptors(ATreceptors).Thisleadsto1(FIG. 1).anarrowingofbloodvesselsandanincreaseinbloodThediscoveryofrenin1byTigerstedtandBergmanpressure(BP),changesinrenalglomerularandtubularhaditselfre
9、mainedunnoticedformorethan40years,function,inflammationandfibrosisinthekidney,aswellpartlybecaus
