Loss of
orexin neurons is associated with
narcolepsy type 1 (NT1), which is characterized by multiple symptoms including
excessive daytime sleepiness and
cataplexy.
Orexin 2 receptor (OX2R) knockout (KO) mice, but not
orexin 1 receptor (OX1R) KO mice, show
narcolepsy-like phenotypes, thus OX2R agonists are potentially promising for treating NT1. In fact, in early proof-of-concept studies,
intravenous infusion of danavorexton, an OX2R-selective agonist, significantly increased wakefulness in individuals with NT1. However, danavorexton has limited oral availability. Here, we report pharmacological characteristics of a novel OX2R agonist, TAK-994 [N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}
methanesulfonamide sesquihydrate]. TAK-994 activated recombinant human OX2R (EC50 value of 19 nM) with > 700-fold selectivity against OX1R and activated OX2R-downstream signaling similar to those by
orexin peptides in vitro.
Oral administration of TAK-994 promoted wakefulness in normal mice but not in OX2R KO mice. TAK-994 also ameliorated
narcolepsy-like symptoms in two mouse models of
narcolepsy:
orexin/
ataxin-3 mice and
orexin-tTA;TetO
diphtheria toxin A mice. The wake-promoting effects of TAK-994 in
orexin/
ataxin-3 mice were maintained after chronic dosing for 14 days. These data suggest that overall in vitro and in vivo properties, except oral availability, are very similar between TAK-994 and danavorexton. Preclinical characteristics of TAK-994 shown here, together with upcoming clinical study results, can improve our understanding for orally available OX2R agonists as new therapeutic drugs for NT1 and other
hypersomnia disorders. SIGNIFICANCE STATEMENT:
Narcolepsy type 1 (NT1) is caused by a loss of
orexin neurons, and thus an
orexin 2 receptor (OX2R) agonist is considered to address the underlying pathophysiology of NT1.
Oral administration of TAK-994, a novel OX2R agonist, promoted wakefulness in normal mice, but not in OX2R knockout mice, and ameliorated fragmentation of wakefulness and
cataplexy-like episodes in mouse models of
narcolepsy. These findings indicate that TAK-994 is an orally available brain-penetrant OX2R-selective agonist with potential to improve
narcolepsy-like symptoms.