Harnessing GABA and NO mimetic activity for Alzheimer's therapy

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DESCRIPTION (provided by applicant): Neurodegenerative diseases, associated with aging, are multifactorial in origin and progression, eliciting neurological and psychiatric abnormalities. This project is based upon the hypothesis that a drug attenuating several underlying factors whilst treating neurological/psychiatric abnormalities is a preferred therapy for Alzheimer's disease (AD). GT-1061 is a prototype of a new drug class that completed Phase IA clinical trials for Alzheimer's disease (AD); it incorporates structural elements of the clinical neuroprotective agent clomethiazole (CMZ) and the neuroprotective experimental drug, GT-015. CMZ has multiple actions including anti-neuroinflammatory and GABA mimetic. GT-015 is a NO (nitric oxide) mimetic that has pleiotropic actions including cognition enhancement. We propose that a molecule that incorporates NO mimetic properties and harnesses the neuroprotective anti-neuroinflammatory and GABA mimetic properties of CMZ can be optimized as a disease modifying and procognitive agent for AD. The objective of the proposal is to use a small focused synthetic library of CMZ analogs assayed first in cell culture and then in animal models to maximize the anti-inflammatory properties, retaining GABA mimetic activity. Neuroprotection in vitro and in vivo will be studied in a transgenic mouse model of AD (AD-Tg). The new lead compounds, optimized CMZ analogs, will form the structural basis for new nitrates, NO chimeras, designed to retain neuroprotective and GABA nmimetic activity and to add ancillary NO mimetic activity. A small library of CMZ-derived NO chimeras will be assayed in cell culture and in animal models, including behavioral and histological measurements. In order to arrive at the two NO chimera drug candidates that are deliverables from this project, we will incorporate into our drug design strategy bioassay data from: sedative and procognitive activity in animal models; physicochemical properties, gross toxicology, pharmacokinetics, and blood pressure effects in rats. The drug candidates must be able to restore normal synaptic funtion in AD-Tg mice. Finally, a preformulation strategy defined for GT-1061 will be applied to the 2 novel NO chimera drug candidates in order to select one candidate in a form suitable for future cGMP synthesis and pre-IND ADME/tox