Lead Optimization of Peripheral CB1 Neutral Antagonists for Renal Diseases

RESEARCH andampRELATEDUnitPROJECT SUMMARY ABSTRACT In response to PAthe aim of this Phase I STTR proposal is to optimize and develop peripherally actingcannabinoidreceptorCB Rneutral antagonists displaying favorable therapeutic profiles for treating diabetic nephropathyDNDN is a chronic diabetic kidney disease and affectstypeand typediabetic patientsIt is characterized by persistent albuminuria and abnormal renal function as represented by an abnormality in serum creatininecalculated creatinine clearanceprogressive decline in the glomerular filtration rateGFRand hypertensionDN can ultimately lead to end stage renal diseaseESRDwherein a patient would require dialysis or a kidney transplantThe endocannabinoid systemECShas been implicated in the pathogenesis of DNcongruent with the observation that CB R expression is dramatically increased in the kidney after the onset of DNNotablythe pathophysiology of obesity related renal dysfunction also contributes to DNThis is associated with hyperglycemiahypertensiondyslipidemia and dietary protein intakeWe have recently shown that blockade of CB R is beneficial for treating DN whereinAMa peripherally acting CB R neutral antagonist was shown to conserve renal structure and functionIn a separate studyAMwas also shown to reduce renal fibrosisOur group previously showed that AMhas positive metabolic effectsThese data together indicate that peripheral CBblockade combined with neutral antagonism represents a novel mode of pharmacotherapy for treating DN and diabetes related complications including stabilizing metabolic parameters and treating renal fibrosisAMdisplays improved safety profiles when compared to known brain penetrant CB R inverse agonists and is the only validated pharmacological tool available in this classAMcan be used as an excellent prototype for the development of improved druggable candidates for treating DNBased on our preliminary studieswe have now identified an early lead which displays the beneficial properties as AMIn this STTR proposalaimand aimwill focus on the optimization of our early lead and to develop selective high affinity CBneutral antagonists displaying improved aqueous solubilitiesAimwill comprise testing of compounds in vivo so as to quantify them in brain and plasma and identify non brain penetrants displaying improved oral bioavailabilitiesSubsequentlywe will focus on testing the optimized leads in validated pre clinical rodent models of DN that are considered perfect translational models to humansThese studies will be planned based on a collaboration with the Department of MedicineBrigham and Womenandapos s Hospital and Harvard Medical SchoolIf successfulPhase II of this grant will focus on identifying a candidate andbackups and then advancing the lead candidate towards IND enabling studies while partnering with a major biotechnology company RESEARCH andampRELATEDUnitPROJECT NARRATIVE The goal of this Phase I STTR proposal is to develop peripherally restricted CB R neutral antagonists for treating diabetic nephropathyDNThere is no specific FDA approved medication that targets DNprevents end stage renal diseaseESRDor renal fibrosiswhile displaying positive metabolic effectsIn this regardan agent that can stop or delay the progression of DN and prevent overt DNoffers a major therapeutic advantageThe proposed research aims towards developing a treatment for DN using a new and novel mode of pharmacotherapy and satisfies a therapeutic need that is relevant to NIDDKandapos s mission