Unmet Medical Needs Narcolepsy and Primary Hypersomnia

There is a key need for nonstimulant and, by extrapolation, nonscheduled NCEs to replace amphetamine-like agents. The success of modafinil, which has been described as producing 'a sense of ''being awake,'' compared with the experience being ''stimulated on sympathomimetcs,''10 has prompted a resurgence of activity in the search for novel NCEs that is only limited by a lack of knowledge of the mechanism of action of this novel wake-promoting agent. The search for novel therapeutics that address fundamental disease biology beyond targeting symptomatology are starting to yield novel agents. Medicinal chemistry approaches for the identification of selective orexin antagonists are still in the early stages but compounds of potential interest are starting to emerge that can be used to probe the orexin-1 receptor SB-334867, 40, and SB-408124, 41, show high selectivity (50-100-fold) for OX1 relative to OX2 and other GPCR targets, and with relatively high antagonist potency.95


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