Novel Thioderivatives as Neuroprotective Anticonvulsants Abstract:
The aim i s to discover novel lead compounds that provide a disease- modifying therapeutic for the treatment of epilepsy. The ideal candidate molecules generated by this program will exhibit both anti-seizure activity in animal models of epilepsy as well as neuroprotective properties from glutamate or hydrogen peroxide in cultures derived from an area of the brain that is vulnerable to seizures and resulting neuronal damage. The objective of the phase one studies is to generate """"""""proof of concept"""""""" compounds that will exhibit the desired properties of neuroprotection and efficacy in an animal model of epilepsy. This objective directly coincides with the solicitation topic for new treatments for epilepsy as described by the NINDS. The chemistry will involve a highly directed synthesis of analogues of an existing experimental anticonvulsant. The proposed compounds will contain one or more of the following domains: sulfamide or a sulfur-containing heterocycle. The novel, sulfur- containing compounds will be designed and synthesized for a four-step qualifying sequence of testing: in vitro toxicity, in vitro neuroprotection, metabolic stability and in vivo anti-seizure consisting of the maximal electroshock seizure test in mice. The innovative aspects of this program are two-fold: 1) the novelty of the chemical series focused on the sulfur-containing derivatives with established anti-seizure activity;and 2) the use of hippocampal neurons as the primary screening system to detect both protective and toxic properties of the novel compounds. Devising compounds with greater metabolic stability and safety than the parent compound is a priority. While the emphasis of the first phase is to generate a library of promising neuroprotective, anti- seizure compounds, a limited number of tests will be conducted to assess solubility, drug permeability and potential cardiovascular liabilities (hERG channel interactions). Compounds emerging from the phase I portion of this program will be advanced to animal models of refractory epilepsy and for detailed studies of toxicological and pharmacokinetic properties that will comprise the phase II of discovery. The phase I project is critical to the long-term purpose of discovering new antiepileptic drugs that are both disease-modifying with neuroprotective properties and effective in treating patients that are refractory to current treatments. The long-term business strategy is to devise lead compounds that are ready for licensing in phase I clinical trials.
Current estimates indicate that 25% of people suffering from epilepsy receive no effective treatment for their seizures from today's available drugs. With the goal of meeting this unmet medical need and eventually to block epileptogenesis, we seek to discover novel compounds that are both neuroprotective and also possess anti-seizure properties.
| Smith, Garry R; Brenneman, Douglas E; Zhang, Yan et al. (2014) Small-molecule anticonvulsant agents with potent in vitro neuroprotection and favorable drug-like properties. J Mol Neurosci 52:446-58 |
| Brenneman, Douglas E; Smith, Garry R; Zhang, Yan et al. (2012) Small molecule anticonvulsant agents with potent in vitro neuroprotection. J Mol Neurosci 47:368-79 |
