SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis 英文参考文献.docVIP

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SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis 英文参考文献.doc

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SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis 英文参考文献

SCYX-7158,anOrally-ActiveBenzoxaboroleforthe TreatmentofStage2HumanAfricanTrypanosomiasis RobertT.Jacobs1*,BakelaNare1,StephenA.Wring1,MatthewD.Orr1,DaitaoChen1,JessicaM.Sligar1, MatthewX.Jenks1,RobertA.Noe1,TanaS.Bowling1,LukeT.Mercer1,CindyRewerts1,EricGaukel1, JenniferOwens1,RobinParham1,RyanRandolph1,BethBeaudet1,CyrusJ.Bacchi2,NigelYarlett2, JacobJ.Plattner3,YvonneFreund3,CharlesDing3,TsutomuAkama3,Y.-K.Zhang3,RetoBrun4 ,Marcel Kaiser4,IvanScandale5,RobertDon5 1SCYNEXIS,Inc.,ResearchTrianglePark,NorthCarolina,UnitedStatesofAmerica,2HaskinsLaboratory,PaceUniversity,NewYork,NewYork,UnitedStatesofAmerica, 3Anacor Pharmaceuticals, Inc., Palo Alto, California, United States of America, 4Swiss Tropical and Public Health Institute, Basel, Switzerland, 5Drugs for Neglected Diseasesinitiative,Geneva,Switzerland Abstract Background:HumanAfricantrypanosomiasis(HAT)isanimportantpublichealthprobleminsub-SaharanAfrica,affecting hundredsofthousandsofindividuals.Anurgentneedexistsforthediscoveryanddevelopmentofnew,safe,andeffective drugstotreatHAT,asexistingtherapiessufferfrompoorsafetyprofiles,difficulttreatmentregimens,limitedeffectiveness, andahighcostofgoods.Wehavediscoveredandoptimizedanovelclassofsmall-moleculeboron-containingcompounds, benzoxaboroles,toidentifySCYX-7158asaneffective,safeandorallyactivetreatmentforHAT. Methodology/PrincipalFindings:Adrugdiscoveryprojectemployingintegratedbiologicalscreening,medicinalchemistry andpharmacokineticcharacterizationidentifiedSCYX-7158asanoptimizedanalog,asitisactiveinvitroagainstrelevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense, is efficacious in both stage 1 and stage 2 murineHATmodelsandhasphysicochemicalandinvitroabsorption,distribution,metabolism,eliminationandtoxicology (ADMET) properties consistent with the compound being orally available, metabolically stable and CNS permeable. In a murine stage2study, SCYX-7158is effective orallyat dosesaslow as12.5mg/kg(QD67 days). Invivopharm