Beruflich Dokumente
Kultur Dokumente
PHARMACY753,WINTER2007
MEDICINALCHEMISTRY/PHARMACOLOGY
CARDIOVASCULARAGENTS
II:SYMPATHOLYTICANDVASODILATOR
ANTIHYPERTENSIVEAGENTS
Dr.J.F.Stevens
Readingassignment:WilsonandGisvold11thed.,pp650655
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ANTIHYPERTENSIVEAGENTS
INTRODUCTION:
HypertensionariseswhenthearterialBPissustainedatanelevatedlevel.Over60millionpersonsinthe
UShaveelevatedBPanditiscontributingfactorin>106deaths/yr.
ArterialBPisregulatedbynumerousfactors,including:
heartrateandstrokevolume
resistanceofperipheralvascularnetwork
bloodvesselelasticity
bloodvolumeandviscosity
endogenouschemicals/hormones
BecausemultipleregulatorysystemscontrolBP,coupledwiththecomplexityofthefactorscausing
hypetension,therapeuticagentsthatacttoBPworkbyavarietyofmechanismsandactatanumberof
differentsites
CLASSESOFANTIHYPERTENSIVEAGENTS
SympatholyticAgents
peripherallyacting
centrallyacting
Vasodilators
Reninangiotensinsystemmodulators
Ca2+antagonists
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Diuretics
PERIPHERALLYACTINGSYMPATHOLYTICAGENTS
adrenergicneuronblockingagents
Rauwolfiaalkaloids
Usedforcenturiestotreatinsectbites,fever,insomniaandinsanity
MajoractivecomponentisReserpine
H3 CO
N
H H
H
H3 CO 2C
OCH3
O
OCH3
OCH3
OCH3
Reserpinemechanismofaction
Causesdepletionofbiogenicamineneurotransmittersfromperipheraladrenergicneurons
Twoproposedmechanisms
reserpineinhibitsNTtransportintothestoragevesicles
reserpinedestroystheNTstoragevesicles
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CNSsideeffects
Guanethidine(ISMELIN)
N
H
N
Guanedrel(HYLOREL)
NH
NH
O
NH 2
O
Mechanismofaction
ActivelytransportedintotheneuronviareuptakemechanismforNE
InitialstepistobindtostoragevesiclesandinhibitNErelease
Displacestheneurotranmitterfromthevesicle
Theseagentsdisplaysomepropertiesofafalseneurotransmitter
foundinstoragevesicles
depletelevelsofendogenousNT
releaseduponstimulation
exhibitlowaffinityforpostsynapticNTreceptor
HowevertheinitialsympatheticblockoccurspriortoNEdepletion
NoCNSsideeffects
N
H
NH 2
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NOTE:relianceonactivetransportmechanismforentryintoneuronsrequirestheseagentsnotbetaken
concurrentlywithdrugsthatblockNTreuptake.
adrenergicantagonists
Blocking1adrenergicreceptorsinhibitsvasoconstrictioninducedbycatecholamineNTs.
Vasodilationoccursinbotharterialandvenoustissues.
Piperazinylquinazolines
GeneralStructure
N
H3CO
N
N
H3CO
NH2
Prototypeisprazosin(MINIPRESS)
O
N
H3CO
H3CO
N
NH2
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1selective
Goodoralavailability
Onsetofactionin23hrs
Metabolizedprimarilybydemethylationandglucuronidation
StructureActivityRelationships
thepiperazinyl6,7methoxyquinazolinenucleusisoptimal
replacementoftheOMegroupswithmethylsactivity
replacementofOMegroupswithH,OHormethylendioxygroupeliminatesactivity
Groupsonthepiperazineringcanvary
O
O
R=
R=
Doxazosin(CARDURA)
Terazosin(HYTRIN)
Otherantagonistsindicatedasantihypertensives
Phenoxybenzamine(DIBENZYLINE)
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CH3
O
N
Cl
Phentolamine(REGITINE)
H 3C
H
N
N
N
OH
Tamsulosin(FLOMAX)
O
O
O
N
H
tamsulosin
>selective1Areceptorantagonist
O
>fortreatmentofbenigneprostatehyperplasia(VSMrelaxation
S
inprostaticregiontoimprovemicturition)
NH2
>lessorthostatichypotension
AdrenergicAntagonists
Complexandmultiplemechanismsofactionthatleadtoadecreaseinbloodpressure
Include:
inhibitionofcentralmechanismscontrollingBP
reductionincardiacoutputbyactingdirectlyatreceptorsintheheart
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inhibitionofreninreleasebyantagonizingreceptorsinthekidney
receptorantagonistsareusedtotreatallgradesofhypertension
mostappeartobeequallyeffective
commonlycombinedwithdiureticsorACEinhibitors
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CENTRALLYACTINGSYMPATHOLYTICS
Firstgenerationwereadrenergicagonists
Originalproposalwasthattheystimulatedcentral2receptorswhich
inhibitsreleaseofNE
reducessympatheticoutflowfromCNS
PrototypeisClonidine(CATAPRES)
Cl
Cl
N
NH
HN
Doesnotproduceorthostatichypotensionassociatedwithantagonists
CanactcentrallyANDperipherally
Atdosesgreaterthanrequiredforcentraleffectsclonidinecanactivatereceptorsinvascular
smoothmuscleandcausevasoconstriction.
Theresultisalossofthetherapeuticeffectathighdoses
ClonidineSAR
X
HN
N
X
NH
N
NH
X=X=H
NH
ED20(mg/kg)
>3.0
X=Cl;X=H
1.0
X=X=Cl
0.01
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X=X=Br
0.045
X=X=F
>3.0
X=X=Methyl
0.1
X=X=Ethyl
>3.0
X=X=CF3
0.06
ED20referstotheIVdosenecessarytolowerthebloodpressureby20mmHgintherabbit.
Clonidinemetabolism:parahydroxylationofphenylringandglucuronidationofhydroxylgroup.
MetabolitescannotpassBBBandhavenoantihypertensiveeffect.
Otheragonists
Guanabenz(WYTENSIN)
Guanafacine(TENEX)
Cl
Cl
HN
CH
N
HN
NH 2
NH 2
NH
NH
Cl
Cl
Methyldopa(ALDOMET,METHYLDOPATEHYDROCHLORIDE)
HO
HO
NH 2
CH 3
CO 2H
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mechanismofaction
firstbelievedtofunctionasaperipheralfalseneurotransmitterafterconversiontoMeNE
laterevidencepointedtocentralactivity
dopadecarboxylaseinhibitorstudies
dopadecarboxylaseinhibitorsabletoaccesstheCNSblockmethyldopaantihypertensive
action
inhibitorsthatcantcrossBBBhavenoeffectonantihypertensiveaction
centrallyactingantagonistsblockantihypertensiveeffectofmethyldopa
SecondGenerationCentrallyactingSympatholytics
Discrepanciesnoticedwithcentral2agonistMOAforagentslikeclonidineandguanabenz
whywereguanabenzandguanfacine10xlesseffectiveantihypertensivesthanclonidinebuthad3
10xhigheraffinityfor2receptorandweremore2selective?
whydidthelatercompoundsstillexhibitthesamesideeffectprofileasclonidineiftheyweremore
2selective?
Radiohistochemicalstudiesshowthecentralsitesofactionforclonidineareintheventrolateralmedulla
foundthisregionregionofthebraindoesnotcontainmany2receptors
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foundthatclonidinealsobindstoanovelclassofreceptors
selectiveforimidazoleandimidazolinecontaining
compoundsandtheVLMisrichinthesereceptors.
Distinctfromadrenergicandhistaminergicreceptors.
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HN
HN
N
R
imidazole
N
R
imidazoline
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I1imidazolinereceptors
HighlyselectiveI1agonistshavebeendeveloped
SomeareequipotenttoclonidineindecreasingBPbutshowlowerincidenceofdrymouth/sedation
Moxonidine
Cl
HN
H3C
NH
N
OCH3
SiteofactionisVLM
AgonismoftheI1receptorresultsinloweredcatecholaminesecretionandareductioninrenin
andaldosteronelevels
highestaffinityatI1receptorofknownagonists
affinityforI1vs2sitesis40200xgreater
longduration
notmetabolizedtoanysignificantextent
lesspotentialforBPrebounduponwithdrawal
efficacyissimilartoACEinhibitors,Ca2+antagonistsandblockersatloweringBP
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Rilmenidine(HYPERIUM)
O
N
NH
Slightlylesspotentthanmoxonidine
Samepharmacologicalprofile
ARTERIALVASODILATORS
Agentsactingdirectlyonsmoothmuscletoreducearterialtonewithoutaffectingautonomicnervous
system
Effectisoftencompensatedforbysympatheticreflexessoblockersarecommonlycoadministered
Hydralazine(APRESOLINE)
NHNH 2
N
N
OneoffirstmarketedorallyactiveantihypertensivesinUS
lostpopularityduetosideeffectprofile
addingonablockersothatdoseofhydralazinecouldbereducedimprovedcompliance
appearstoaffectCa2+entryandCa2+releasefromintracellularstores
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Diazoxide(HYPERSTAT)
CH 3
Cl
NH
O
orallyavailablebutonlygivenIV
OriginatedfromthiazidediureticSARstudies
initiallybelievedthatthedecreaseinBPobservedwiththiazideswasonlyaresultofdiuresis
removalofsulfonamidefrom7positionofthiazidecoreeliminateddiuresisbutsomeof
thesecompoundsretainedantihypertensiveactivity
ledtothedevelopmentofdiazoxide
Sideeffects:
cancausehyperglycemia
extendedusecanresultinhypertrichosis
Minoxidil(LONITEN,ROGAINE)
Usedincasesofsevereorrefractory
HTN
N
H 2N
Sideeffectsincludereflextachycardia
NH 2
Na+andH2Oretention
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hypertrichosis
MinoxidilrequiresmetabolicactivationtotheOsulfate
PAPS=3phosphoadenosine5phosphosulfate
Sulfotransferase
PAPS
H2N
N
O
NH2
O
S
Cluestorequirementforactivation
minoxidilhasnodirectactiononvascularsmoothmuscleinvitro
3060minutedelayintheonsetofantihypertensiveaction
Pinacidil
CH3
WelldocumentedK+channelopener
MarketedextensivelyoutsidetheUS
NC
SoldastheracemicmixturebutitistheR()isomerthatisactive.
HN
N
CH3
CH3
CH3
NH
pinacidil
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MISCELLANEOUSNEWANTIHYPERTENSIVEAGENTS
ANDNEWTARGETSFORTREATINGHYPERTENSION
Fenoldopammesylate(Corlopam)
Cl
HO
ReleasedintheUSin1999forusintheshorttermcontrolofsevere
hypertensioninahospitalsetting
NH
HO
Rapidonsetandlongduration
ActsasaperipheraldopamineD1receptoragonisttocausesystemic
vasodilation
Cantcrossthebloodbrainbarriersonocentraldopaminergiceffects
HO
Alsohassomeaffinityfor5HT1and5HT2receptors
Foundtobemorepotentthannifedipineinaheadtoheadtrial
Ketanserin
O
O
serotonin5HT2receptorantagonist
veryeffectiveatreducingBP,especiallyinelderly
5HT2antagonismalonecannotexplainantihypertensive
activity
N
H
V1VASOPRESSINRECEPTORANTAGONISTS
Vasopressinisapeptideamidehormonewithvasoconstrictingaction
Nonpeptideantagonistsareunderdevelopment
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N
O
ketanserin
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ENDOTHELINRECEPTORANTAGONISTS
Endothelins(ETs)areafamilyofpeptideswithcomplexactionsonvascularsmoothmuscle
ET1isamorepotentvasoconstrictorthanangiotensinII
ETAreceptormediatesvasoconstrictionandETBreceptormodulatesvasodilationandantiplateletactivity
SeveralnonpeptideETAantagonistswentintoclinicin1995and1996
Bosentan(2001)
O
S NH
O
N
N
N
N
OCH3
O
O
OH
Endothelinconvertingenzymeisalsoatargetfordevelopingnewantihypertensiveagents.
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