有机小分子探针合成与脱保护文献

J.Med.Chem.2010,53,6653–66806653

DOI:10.1021/jm100669j

OrallyActiveMMP-1Sparingr-Tetrahydropyranylandr-PiperidinylSulfoneMatrix

Metalloproteinase(MMP)InhibitorswithEfficacyinCancer,Arthritis,andCardiovascularDisease

DanielP.Becker,*ThomasE.Barta,LouisJ.Bedell,TerriL.Boehm,BrianR.Bond, JefferyCarroll,ChrisP.Carron, GaryA.DeCrescenzo,AlanM.Easton,JohnN.Freskos,ChrisL.Funckes-Shippy,MarciaHeron,SusanHockerman,

CarolPearcyHoward,JamesR.Kiefer,§MadeleineH.Li,KarlJ.Mathis,JosephJ.McDonald,PramodP.Mehta,GraceE.Munie,TeresaSunyer,CraigA.Swearingen,ClaraI.Villamil,DeanWelsch,JenniferM.Williams,YingYu,andJunYao

PfizerResearch,700ChesterfieldVillageParkway,St.Louis,Missouri63198. Contactforcardiovascularbiology:E-mail,bbond4@slu.edu.

Contactforcancerbiology:E-mail,chris.p.carron@http://www.1mpi.com.Currentaddress:MonsantoCompanyC3NG,800NorthLindberghBoulevard,St.Louis,MO63167.§Contactforcrystallographyandcomputationalchemistry:E-mail,james.kiefer@http://www.1mpi.com.Contactforarthritisbiology:E-mail,dean.j.welsch@http://www.1mpi.com.ReceivedJune2,2010

)

R-Sulfone-R-piperidineandR-tetrahydropyranylhydroxamateswereexploredthatarepotentinhibi-torsofMMP’s-2,-9,and-13thatspareMMP-1,withoralefficacyininhibitingtumorgrowthinmiceandleft-ventricularhypertrophyinratsandinthebovinecartilagedegradationexvivoexplantsystem.R-Piperidine19v(SC-78080/SD-2590)wasselectedfordevelopmenttowardtheinitialindicationofcancer,whileR-piperidineandR-tetrahydropyranylhydroxamates19w(SC-77964)and9i(SC-77774),respectively,wereidentifiedasbackupcompounds.

Introduction

Matrixmetalloproteinases(MMPsa)areafamilyofzinc-dependentendopeptidasesthatareinvolvedintheremodelinganddegradationofallcomponentsoftheextracellularmatrix(ECM)andhavekeyrolesindeve-lopment,morphogenesis,boneremodeling,woundheal-ing,andangiogenesis.1Thefirstmatrixmetalloproteinase,acollagenase,wasdiscoveredbyGrossandLapierein1962,explainingthemetamorphosisofatadpoleintoafrog.2,3However,inappropriateMMPactivityhasbeenimplicatedinanumberofdiseasestatesincludingtumorgrowthandmetastasis,4-6degradationofarticularcarti-lageinarthritis,7-9andtissueremodelingandweakeningoftheleftventricularwallincongestiveheartfailure.10-13Toamelioratediseaseprogressionresultingfrominap-propriatematrixremodelingmediatedbyMMPsinthese

*Towhomcorrespondenceshouldbeaddressed.Phone:773-508-3089.Fax:773-508-3086.E-mail:dbecke3@luc.edu.Address:LoyolaUniversity,6525NorthSheridan,Chicago,IL60626.a

Abbreviations:ADME,absorption,distribution,metabolismandexcretion;API,activepharmaceuticalingredient;Ar,aryl;Arg,argi-nine;bid,twicedaily;BNCD,bovinenasalcartilagedegradation;CY,cyclophosphamide;DMAC,dimethylacetamide;DSC,differentialscanningcalorimetry;Dulbecco’sModifiedEagleMedium;DMF,dimethylformamide;EA,ethylacetate;EDC,1-ethyl-3-[3-dimethyl-aminopropyl]carbodiimidehydrochloride;ES,electrospray;F,female;Glu,glutamicacid;HOBt,N-hydroxybenzotriazole;HPLC,highpres-sureliquidchromatography;HRMS,high-resolutionmassspectrome-try;IL,interleukin;Ki,inhibitionconstant;LV,leftventricular;M,male;MI,myocardialinfarction;MIR,multipleinternalreflectanceinfraredspectroscopy;MMP,matrixmetalloproteinase;MMPi,matrixmetallo-proteinaseinhibitor;mpk,milligramsperkilogram;MSS,musculoske-letalsyndrome;NMM,N-methylmorpholine;OA,osteoarthritis;PDB,ProteinDataBank;pk,pharmacokinetics;PyBroP,bromo-tris-pyrro-lidino-phosphoniumhexafluorophosphate;QD,onceperday;rmsd,root-mean-squaredeviation;SAR,structure-activityrelationship;SEM,standarderrorofthemean;THF,tetrahydrofuran;THP,tetra-hydropyranyl;TIMP,tissueinhibitorofmatrixmetalloproteinase;TLC,thin-layerchromatography;TMS,

有机小分子探针合成与脱保护文献

tetramethylsilane.

r2010AmericanChemicalSociety

Figure1.MMPInhibitors.

variousdiseasestates,MMPinhibitors(MMPi’s)havebeenextensivelyexplored.4,5,14-16

However,patientsdosedwithbroad-spectrumMMPi’sincludingmarimastat(1,Figure1)sufferstiffeningofthejointsreferredtoasmusculoskeletalsyndrome(MSS)12andthebroad-spectruminhibitormarimastatinducesjointfibroplasiainrats.17TheunderlyingcauseofMSSobservedclinicallywithbroad-spectruminhibitorshasbeenhypothesizedtobeduetoinhibitionoftheconstitu-tiveinterstitialcollagenaseMMP-118-21orsheddasessuchasTACE22oracombinationofthosemetalloproteinases.Hence,recenteffortshavebeentowardthediscoveryanddevelopmentofhighlyspecificMMPinhibitorsthatspareoff-targetisozymes.23-26

PublishedonWeb08/20/2010

http://www.1mpi.com/jmc

)

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