Development of an adenosine A1 receptors agonist, MRS5474 for the treatment of chronic depression

Development of an Adenosine AReceptor agonistMRSfor the treatment of chronic depression Project Summary Depression is a common mental disorderwhich can be chronic or recurrentmarkedly tarnishing a person s ability to function in their normal lifePeople with a depression can feel emptysadhelplessrestlesshopelessanxiousworthlessguiltyirritableashamed or suicidalThey may lose interest in routine work or physical activitiesThey show appetite disorderproblems concentratingremembering details or making decisionsIt has also been shown that healthy people may exhibit sub clinical levels of depressive symptomsBecause of their impact on the society and widespread prevalencedepressive symptoms are a significant public health concernNearlyof the populationshow depression like symptoms at some point in their livesCurrentlythere aremillion people worldwide andmillion people in the US affected by depressionand the scope of the population affected by depression is gradually expandingThe estimated market for antidepressants was $billion and will grow to $billion by the yearDespite recent advances in pathophysiological hypotheses such as alterations in neuroplasticityneurogenesisand neuroimmunological regulationcurrent treatments lack rapid clinical efficacy limiting the abilityfor exampleto bring instant relief needed with suicidal patientsThereforethere is a need for the rapid treatment of depressionThe adenosine signaling pathway activated by sleep deprivation has shown rapid benefits in preclinical and clinical studiesIn particularsleep deprivation upregulates adenosine AreceptorsA Rin mice and humansDrJacobson and his group have identified a compound MRSas a potent smallmolecule A R agonist with exceptional drug like propertiesIt is metabolically stableorally bioavailable and has an excellent safety profile in miceOur collaboratorDrBiberhas shown that A R knockout mice exhibit an increased depressive like behavior and were resistant to the antidepressant effects of sleep deprivationIn contrasthe demonstrated that upregulation of A R had pronounced acute and chronic resilience toward depressivelike behavior in various testsFurthermorethey also showed that increased expression of homer a is a final common pathway mediating the antidepressant effects of different antidepressant treatments including the A R agonistThe A R agonist MRSinduced a rapid antidepressant effects in animal models of transgenic mice with intraperitonealIPadministrationIn summaryMRShas great potential to be a rapidefficacious and safe antidepressant with a unique mechanism of actionThe expression of Homer a and ERKwill serve as biomarkers for preclinical and clinical studiesIn this Fast Track proposalwe will first establish thatMRShas good BBB penetrationBrain Plasma ratiodirect relationship between exposure of MRSand effects on Homer a expression levels and ERK activityA R antidepressant effects of MRSin the CDM with oral administration andan excellent safety profileIn the Phase IIwe will continue with IND enabling studies to ensure that MRShas all the attributes to become a successful antidepressant drug and will file IND application for clinical trials Project Narrative Depression is a serious medical illness that afflicts more thanmillion people in the USAdenosine AreceptorsA Rplay a key role in neuroprotection and enhanced AA R function has shown antidepressant effects in preclinical and clinical studiesThe goal of this project is to develop MRSa potent and orally bioavailable A R agonist for the treatment of depression