SBIR-STTR Award

Studies on the metabolism and pharmacology of ADD17014, a novel triazoline anticonvulsant, have led to the discovery of the aminoalkyl heterocycles as a unique class of anticonvulsant agents. Initial work on aminoalkylpyridines indicate that they are nontoxic, and highly effective by the oral route, with protective indices greater than 20. They impair presynaptic release of L-glutamate and also function as noncompetitive NMDA antagonists that inhibit with great selectivity and specificity, the sigma receptor, but show no affinity for PCP receptors. NMDA receptor overstimulation by glutamate is implicated in epileptogenesis and epilepsy. Thus NMDA antagonists will provide prophylaxis and seizure protection. There is a definite need for safer, orally active NMDA antagonists, to afford effective therapies for the epilepsies. Our long-term objectives are to develop clinically useful, nontoxic antiepileptic drugs from anticonvulsant aminoalkyl heterocycles by rational analogue synthesis of "active leads" using various basic structural modifications. We will initiate analogue synthesis of lead aminoalkyl-4-pyridines, which will include two basic structural variations. Resulting data will be used to guide further analogue synthesis in Phase II. Synthetic procedures have been developed. Excessive levels of glutamate are suspected not only in epilepsy, but in several other neurological disorders, e. g. stroke. Thus, nontoxic, orally active NMDA antagonists developed from aminoalkyl heterocycles, have good potential for commercial application as clinically useful anti-epileptic drugs and also as neuroprotective agents in other neurological disorders.Awardee's statement of the potential commercial applications of the research:The aminoalkylpyridine heterocycles are non neurotoxic, orally active antiepileptic agents. They act by impairing glutamate release and function as noncompetitive NMDA antagonists that selectively inhibit the sigma receptors with no affinity for PCP receptors. They have commercial potential as safer, nontoxic, clinically useful antiepileptic drugs, and also as neuroprotective agents in other neurological disorders, such as stroke and Alzheimer's disease, where excessive glutamate is implicated.National Institute of Neurological Disorders and Stroke (NINDS)

The identification of the pharmacophore of the triazoline anticonvulsants led to the discovery of the sigma-selective aminoalkylpyridines (AAPs), as potent orally active anticonvulsant agents, far superior to the triazolines; they are highly effective in the rat MES seizure test, with long duration of action and no apparent signs of drug-induced motor toxicity when orally administered. The AAPs have no affinity for the PCP receptor and seem to act by impairing glutamate release: thus the toxic side effects of NMDA antagonists are absent in the AAPs. NMDA receptor overstimulation by excessive glutamate release occurs during epileptic seizures and is implicated in epileptogenesis and epilepsy. Thus NMDA/glutamate antagonists will provide prophylaxis and seizure protection, but currently no safe, orally effective NMDA/glutamate antagonists exist. Our long-term objectives are thus to develop from among the anticonvulsant AAPs, therapeutically useful antiepileptic drugs by rational analogue synthesis of active AAP leads, using 3 basic structural modifications. Variations of the heterocyclic unit and the alkyl chain, during Phase-I, have led to 6 active leads.The objectives of Phase-II are to study 4 different structural variations on the terminal amino group of the 6 AAP leads, and to prepare the R and S enantiomers of the two most active AAP racemates and determine enantiomeric specificity and activity. The most promising AAP analogue/ enantiomer emerging from these studies will be subjected to 30- and 90-day toxicity studies in the rat and the dog to advance this compound to the IND status in early Phase-III. The nontoxic orally effective glutamate antagonists, developed from AAPs, have good commercial potential as clinically useful antiepileptic drugs and also as neuroprotective agents in other neurological disorders such as stroke and Parkinson's disease where excessive glutamate levels are suspected.National Institute of Neurological Disorders and Stroke (NINDS)