Target Identification for Novel Small Molecule Therapeutic for Alzheimer's disease

ABSTRACT Traditional approaches to drug development for Alzheimer s disease are becoming increasingly expensive and in many cases disappointingly unsuccessful Based on preliminary in vitro and in vivo studies we have identified a novel small molecule methyl dimethyl oxo dihydrobenzo c naphthyridine carboxylate UK that significantly decreases A production and pro inflammatory M cytokines while simultaneously inducing anti inflammatory M a cytokines Although our preliminary data show UK effectively modifies critical neuropathologic features of AD with no apparent adverse effects the drug target remains unclear Based on preliminary in silico modeling and in vitro data that suggest UK may modulate mGluR an allosteric glutamate receptor recently identified as a potential therapeutic target in AD the aims of the current proposal are to verify that mGluR is the drug target of UK to quantify the binding constant of UK and to verify that there are no significant off target effects of the drug If successful the data obtained in this proposal will allow further structure activity studies and most importantly establish a specific target for UK Narrative Although current therapeutics for Alzheimer s disease AD show clinical benefit in some patients many do not respond Additionally current drugs do not significantly modify disease progression For these reasons there is a critical need to identify additional therapeutics that can be initiated early in the disease progression to alter progression of the disease Preliminary and future studies described in this proposal aim to define the pharmacologic target of a novel small molecule methyl dimethyl oxo dihydrobenzo c naphthyridine carboxylate UK that shows significant protection against neuroinflammation and amyloid beta peptide processing in well established mouse models of AD pathology