| Description | DoravirineisanovelHIV-1nonnucleosidereversetranscriptaseinhibitorwithIC50valuesof12,9.7,and9.7nMagainstthewildtype(WT)andK103NandY181Creversetranscriptase(RT)mutants,respectively,inabiochemicalassay.Itishighlyspecificwithminimumoff-targetactivities. |
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| Invitro | MK-1439exhibitsgreaterthan10,000-foldselectivitywithrespecttothecellularDNApolymerasesα,ß,andγwithIC50sof>100μM.Inthescreenwithmorethan110proteintargetsincludingenzymes,transporters,ionchannels,andreceptor,MK-1439showsanIC50ofgreaterthan10μMagainstalltargetsexcept5-HT2ß,whereanIC50of2.5μMisnotedinaligandbindingassay.However,the5-HT2ßactivityisnotobservedinafunctionalcell-basedassaymonitoringtheaccumulationofinositol-1-phosphate.Therefore,thebindingactivitydoesnotappeartotranslateintoa5-HT2ßfunctionalresponse.MK-1439doesnotdisplaycytotoxicityinactivatedCD4+Tcells,PBMCs,monocytes,macrophagesproliferatingtransformedcelllines,suchasMT4,SupT1,andHL60celllinesatconcentrationsofupto100μM[1]. |
| Invivo | InratsdosedIVat1mpk(60%PEG200),theclearance(CL)ofMK-1439is5.4mL/min/kgandthehalftimeis4.4hr.Itsvolumeofdistribution(Vd)is2.3L/kg.TheoralbioavailABIlityofMK-1439is57%(doesedPOat5mpk).IndogsdosedIVat0.5mpk,theCLofMK-1439is0.36mL/min/kgandhalf-timeis37hr.TheoralbioavailabilityofMK-1439is52%(doesedPOat1mpk).Overall,ThepharmacokineticprofileofMK-1439inpreclinicalspeciesisfavorable[2]. |
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