Phar753,W07

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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