Nomethiazoles harnessing GABA and NO mimetic activity for Alzheimer s therapy

DESCRIPTION provided by applicant Alzheimerandapos s disease AD occurs in one out of eight Americans of age and affects of the elderly over Current FDA approved drugs provide short term symptomatic relief of AD There is a pressing need to discover new disease modifying medications AD is multifactorial in origin and progression A drug attenuating several underlying factors is a preferred therapy for AD Nomethiazoles are a class of small molecules that address synaptic dysfunction through NO cGMP signaling and harness the neuroprotective and GABA mimetic activities of a methylthiazole MZ pharmacophore Activation of the NO cGMP CREB signaling pathway essential for learning and memory is known to be attenuated in AD brains whereas the MZ pharmacophore provides neuroprotection against neuronal loss and has anti inflammatory actions in the brain Preliminary data show that nomethiazoles reverse cognitive deficits slow A accumulation and provide a positive biomarker profile in AD transgenic mouse models We have positive data on the prototype nomethiazole in four different AD mouse models a U funded drug discovery project that yielded candidate nd generation nomethiazoles and STTR Phase data indicating improved pharmacokinetic properties of of these candidates The objective of this Phase proposal is to de risk and select one drug candidate for future full IND enabling studies In Aims and two advanced mouse models of AD will be used to select the preferred nomethiazole and to provide a unique spectrum of preclinical animal efficacy data E FAD a transgenic mouse model of familial AD incorporating human apoE the major genetic risk factor for AD which increases risk fold and is biased against women and an accelerated oxidative stress model of age related AD that manifests age dependent hallmark AD biomarkers neuronal loss and cognitive decline In Aim rescue and reversal of cognitive decline will be studied in these models In Aim quantitative biomarkers will be measured of target engagement attenuation of AD hallmark pathology and inflammation and rescue of synaptic and neuronal function In Aim drug scale up selected rodent pharmacokinetics toxicology and safety pharmacology will be studied to de risk full IND studies Completion of Aims andamp and Aim will provide persuasive evidence of prospective efficacy and safety respectively PUBLIC HEALTH RELEVANCE Alzheimerandapos s disease AD occurs in one out of eight Americans of age and affects of the elderly over Current FDA approved drugs provide short term symptomatic relief of AD The proposed research will lead to development of new disease modifying medications