title: Small-molecule anticonvulsant agents with potent in vitro neuroprotection and favorable drug-like properties.
abstract: Severe seizure activity is associated with reoccurring cycles of excitotoxicity and oxidative stress that result in progressive neuronal damage and death. Intervention with these pathological processes is a compelling disease-modifying strategy for the treatment of seizure disorders. We have optimized a series of small molecules for neuroprotective and anticonvulsant activity as well as altered their physical properties to address potential metabolic liabilities, to improve CNS penetration, and to prolong the duration of action in vivo. Utilizing phenotypic screening of hippocampal cultures with nutrient medium depleted of antioxidants as a disease model, cell death and decreased neuronal viability produced by acute treatment with glutamate or hydrogen peroxide were prevented. Modifications to our previously reported proof of concept compounds have resulted in a lead which has full neuroprotective action at <1 nM and antiseizure activity across six animal models including the kindled rat and displays excellent pharmacokinetics including high exposure to the brain. These modifications have also eliminated the requirement for a chiral molecule, removing the possibility of racemization and making large-scale synthesis more easily accessible. These studies strengthen our earlier findings which indicate that potent, multifunctional neuroprotective anticonvulsants are feasible within a single molecular entity which also possesses favorable CNS-active drug properties in vitro and in vivo.
authors.affiliation: Fox Chase Chemical Diversity Center, Pennsylvania Biotechnology Center, 3805 Old Easton Road, Doylestown, PA, 18902, USA, gsmith@fc-cdci.com.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Smith
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Brenneman
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yanming
authors.initials: Y
authors.lastname: Du
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018938:Caco-2 Cells; D002478:Cells, Cultured; D020895:Enterocytes / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000927:Anticonvulsants; D018696:Neuroprotective Agents