Structurally Diverse GABA-A ?5 Positive Allosteric Modulators for Treatment of MCI due to AD

The overall objective of this SBIR application is to develop a potentselective and orally active GABA APositive Allosteric ModulatorPAMfor the treatment of Mild Cognitive Impairment due to Alzheimer s DiseaseMCI due to ADThere are currently no approved therapeutics for this indication making this an area of extremely high unmet needThere is strong support from preclinical AD models and human patientsparticularly in this early stage of ADthat neuronal circuits in the hippocampus become excessively active contributing to neuronal pathology and brain dysfunctionAgeneBio s GABA APAM program represents a novel approach to addressing the excess hippocampal activity in this patient population at high risk for dementiaThe concept that reduction of hippocampal overactivity is therapeutically beneficial is supported by recent preclinical and clinical studies using the atypical antiepileptic levetiracetamRanging from research on age associated memory impairment in rodents to clinical studies in patients with amnestic MCIbeneficial effects on key circuits in the medial temporal lobe hippocampus and on memory performance have been demonstrated by treatment at low doses of levetiracetam that reduce hippocampal overactivityThe strong hippocampal localization of GABA Areceptors coupled with its role to control tonic inhibition make GABA APAMs well suited to reduce the excess hippocampal activity in MCI due to ADPreclinical studies in rats with age associated memory loss which show hippocampal overactivity demonstrate that selective GABA Areceptor PAMs are effective therapeutic agents to improve memoryThe screening tree is well definedall assays are in placeand compounds have advanced through the screening treeThe program lead seriesfunded by the Blueprint Neurotherapeutics Networkhas potent and selective GABA APAM compounds with good in vivo efficacy in an age impaired ratHowevershould the lead series falter at any point for reasons independent of mechanism of actionit is critical that a second series be identified that could rapidly be evaluated to mitigate the overall program riskThe purpose of this SBIR grant is to expand the structurally distinctnon BZD second series scaffold to identify potent and selective GABA Acompounds for the treatment of MCI due to AD The GABA APositive Allosteric ModulatorPAMprogram represents a novel approach to Mild Cognitive Impairment due to Alzheimer s DiseaseMCI due to ADa patient population at high risk for dementia andas suchwould address a critical unmet need that will otherwise significantly burden patientscaregivers and the healthcare system in the decades aheadWith no current treatments for this indicationit is critical that novel Discovery Programssuch as the one described in this applicationadvance novel chemical entitiesNCEsat therapeutically relevant targets as rapidly as possibleThe GABA APAM program benefits from clinical and regulatory paths in place for MCI due to AD along with appropriate mechanistic and therapeutic biomarkers making this a program that can advance the goals of the National Plan to Address Alzheimer s Disease