Modafinil: Development and Use of the Compound

Abstract

Modafinil is a wake promoting drug which has transformed the treatment of excessive daytime sleepiness associated with narcolepsy. Its history dates back to 1974 with the identification by two chemists of a French pharmaceutical company, Lafon Ltd., of a new compound, adrafinil, producing hyperactivity in mice. Later on, the kinetic of this substance led to the identification of an active metabolite, modafinil, responsible for an increase of locomotor activity in mice, an increase of wakefulness in the cat, an increase of nocturnal activity in the rhesus monkey, and eventually a reduction of excessive daytime sleepiness in narcoleptic subjects. The compound went through a series of clinical trials, first in France and then, following the purchase of the French company by Cephalon, Inc., in 1993, through large scale clinical trials in Canada and the USA, resulting in an official registration in France in 1992 and in the USA in 1998. In parallel, studies at Stanford progressively disentangled the mechanism of action of the compound, consisting mainly in an inhibitory action on the dopamine transporter (DAT) resulting in dopamine reuptake inhibition. Recently, in 2007, a longer-acting form of modafinil, armodafinil, the R-enantiomer, was approved for the treatment of excessive daytime sleepiness associated with narcolepsy contributing to a refinement of the treatment of narcolepsy.