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1、SynthetichostmoleculesastherapeuticagentsMing-QiangZhangVP&CTO,RocheR&DCentre(China)ThediscoveryofsugammadexOrganonLabsOrganonChemists2Neuromuscularpharmacologyinanaesthesia(1)cholineAChEAChNMB+acetateNMBnAChRNMBblocksthebindingofACh-inducedsignaltransmission,andhenceresultsinmusclerelaxa
2、tion.NMBsareusedclinicallyin-Surgery(paralysisofskeletalmuscles)-Intensivecare(assistmechanicalventilation)-Emergency(intubation)ExamplesofclinicallyusedneuromuscularblockersOAcOAcO++N+NNNAcOHOHHpancuroniumrocuroniumMeOOMe++NOONMeO5OMeMeOOOOMeMeOOMeatracuriumO++NOsuxamethoniumON(depolaris
3、ingNMB!)O3TheneedforNMBreversal•Tospeeduprecoveryfromneuromuscularblockattheendofsurgeryorintensivecare–>65%ofelectivesurgerywasperformedasdayproceduresintheUKand>70%intheUSA–Hospitalcost:$1,237/dayforallmedicalconditions&$2,401/dayinanICU(USA2005).USA2000expenditureforcriticalcaremedicin
4、e~$15-55billion(or~0.5%ofGDP&~13%ofnationalhealthcareexpenditure)•Topreventresidualneuromuscularblockandpost-operativecomplications–Incidenceofresidualparalysis:~38%surgicaloutpatients&47%inpatients–Incidenceofpost-operativecomplications:~5%ofallpatients,upto65%inolderpatients,ofwhich19%l
5、ife-threatening(e.g.pulmonarycomplications)Neuromuscularpharmacologyinanaesthesia(2)cholineAChEAChNMB+acetateAChAChEinhibitorse.g.,neostigminenAChR++NONHONOneostigamineedrophonium4LimitationsofcurrentlyusedNMBreversalagents•Producemajorcardiovascularsideeffects(e.g.arrhythmias,hypotension
6、)duetoactivationofmAChR;•MustbeusedincombinationwithmAChRantagoniststoprotecttheheart,e.g.,atropine;•Residualneuromuscularactivitymustbepresent(e.g.,>10%twitchactivity)beforereversal;•Can’tbeusedtoreversedepolarisingRA,e.g.suxamethonium;•Notsuitableinreversing‘profoundblock’.BioorgMedChem
7、Lett(2002)12,2565BioorgMedChemLett(2002)12,2569BioorgMedChemLett(2002)12,193FromdonepeziltopotentialnewNMBreversalagentsOMeONMeOdonepezilOMeOS+ONNO2MeOOrg24560OrgcodeED50,max.MAP,HR,max.Vagus,mmol/kgreversalmax.D%D%max.D%%donepezil0.21109-22-12+18.5Org245600.004174-
