Nomethiazoles Harnessing GABA and NO mimetic activity for Alzheimer's therapy

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) occurs in one out of eight Americans of age 65 and affects 43% of the elderly over 85. Current FDA-approved drugs only provide symptomatic relief of AD. There is a pressing need to discover newdisease-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 oathway, essential for learning and memory, is known to be attenuated in AD brains. The MZ pharmacophore provides neuroprotection against excitotoxicity and 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: four nomethiazoles have been identified as promising leads for AD therapy. Selection of the preferred drug candidate and a back-up compound for development is the major objective of this STTR phase I study. Optimal pharmaceutical salts of nomethiazoles will be prepared in Aim 1. In Aim 2, drug candidate selection will be guided by drug metabolism and pharmacokinetics (DMPK) studies. Stability in human/rodent plasma and liver microsomes will be investigated and PK profiles generated for nomethiazole and MZ metabolite in brain and plasma after i.p. delivery to mice. In Aim 3, behavioral data will be collected on procognitive, anxiolytic, and sedative effects, to determine the therapeutic window between procognitive and sedative potency. Data comparison of Aims 2 and3 will provide PK/PD correlations. The objective of planned STTR phase 2 studies is to reduce the risk of failure in the clinic by collecting further efficacy and safety data prior to launching full IND-enabling ADMET studies. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) occurs in one out of eight Americans of age 65 and affects 43% of the elderly over 85 with as yet no effective therapeutic approach to slowing disease progression. Nomethiazoles, a new drug class, have shown excellent results in animal models of AD. This STTR Phase 1 proposal will aid in selecting the preferred nomethiazole to move forward towards clinical use as a disease-modifying agent in AD.