| Description | MK-3903isapotentandselectiveAMPKactivatorwithanEC50of8nMforα1β1γ1subunit.Itactivates10ofthe12pAMPKcomplexeswithEC50valuesintherangeof8-40nMandmaximalactivation>50%. | ||
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| Invitro | MK-3903activates10ofthe12pAMPKcomplexeswithEC50valuesintherangeof8-40nMandmaximalactivation>50%.ThecompoundpartiallyactivatespAMPK5(36%max),whichisonlyaminorcomponentofhumanandmouseliver,anditdoesnotactivatepAMPK6,whichisnotdetectedinliver.MK-3903isaweakreversIBLeinhibitorofCYP3A4and2D6inhumanlivermicrosomes(apparentIC50>50μM)anddoesnotexhibittime-dependentinhibitionofCYP3A4activity.MK-3903isnotapotentPXRagoNIST[1]. | ||
| Invivo | ThepharmacokineticsofMK-3903inC57BL/6mice,Sprague–Dawleyrats,andbeagledogswerecharacterizedbymoderatesystemicplasmaclearance(5.0–13mL/min/kg),avolumeofdistributionatsteadystateof0.6–1.1L/kg,andaterminalhalf-lifeof∼2h.IthasloworalbioavailABIlity(8.4%)inC57BL/6mice,buttheoralexposureislaterimprovedusingothervehicles.Oralbioavailabilitiesinratsanddogsareimproved(27-78%).ChronicoraladministrationofcompoundMK-3903robustlyincreasedACCphosphorylationinliverwithmoremodesteffectsinskeletalmuscle.TreatmentofvariousmousemodelswithMK-3903resultsinexpectedalterationsinlipidmetabolismandimprovementsinameasureofinsulinsensitization[1]. |
