Slow Receptor Dissociation Kinetics Differentiate Macitentan from Other Endothelin Receptor Antagonists in Pulmonary Arterial Smooth Muscle Cells 英文参考文献.docVIP

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Slow Receptor Dissociation Kinetics Differentiate Macitentan from Other Endothelin Receptor Antagonists in Pulmonary Arterial Smooth Muscle Cells 英文参考文献.doc

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Slow Receptor Dissociation Kinetics Differentiate Macitentan from Other Endothelin Receptor Antagonists in Pulmonary Arterial Smooth Muscle Cells 英文参考文献

SlowReceptorDissociationKineticsDifferentiate MacitentanfromOtherEndothelinReceptorAntagonists inPulmonaryArterialSmoothMuscleCells JohnGatfield*,CeliaMuellerGrandjean,ThomasSasse,MartineClozel,OliverNayler ActelionPharmaceuticalsLtd.,Allschwil,Switzerland Abstract Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated endothelin system and aberrant contractionandproliferationofpulmonaryarterialsmoothmusclecells(PASMC).ThenovelERAmacitentanhasrecently concludedtestinginaPhaseIIImorbidity/mortalityclinicaltrialinPAHpatients.Sincetheassociationanddissociationrates ofGprotein-coupledreceptorantagonistscaninfluencetheirpharmacologicalactivityinvivo,weusedhumanPASMCto characterize inhibitory potency and receptor inhibition kinetics of macitentan, ambrisentan and bosentan using calcium releaseandinositol-1-phosphate(IP1)assays.Incalciumreleaseassaysmacitentan,ambrisentanandbosentanwerehighly potentERAswithKbvaluesof0.14nM,0.12nMand1.1nM,respectively.Macitentan,butnotambrisentanandbosentan, displayedslowapparentreceptorassociationkineticsasevidencedbyincreasedantagonisticpotencyuponprolongationof antagonistpre-incubationtimes.Incompoundwashoutexperiments,macitentandisplayedasignificantlylowerreceptor dissociation rate and longer receptor occupancy half-life (ROt1/2) compared to bosentan and ambrisentan (ROt1/2 :17 minutesversus70secondsand40seconds,respectively).Becauseofitslowerdissociationratemacitentanbehavedasan insurmountableantagonistincalciumreleaseandIP1assays,andunlikebosentanandambrisentanitblockedendothelin receptor activation across a wide range of endothelin-1 (ET-1) concentrations. However, prolongation of the ET-1 stimulationtimebeyondROt1/2renderedmacitentanasurmountableantagonist,revealingitscompetitivebindingmode. Bosentan and ambrisentan behaved as surmountable antagonists irrespective of the assay duration and