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