molecules of the month

Context. Danavorexton (Takeda, TAK-925) is a CNS-penetrant, injectable OX2 agonist. Orexin receptor (OX1/OX2) antagonists (e.g. daridorexant) are approved for treatment of insomnia. Orexin agonism would be expected to have the opposite effect, promoting wakefulness rather than sleep, which is helpful for patients with narcolepsy (difficulty staying awake). TAK-925 was the first orexin agonist tested in people with narcolepsy type 1. Interestingly, TAK-925 is an injectable molecule, since sleeping or anesthesized patients can’t swallow pills (NCT05025397). The IV molecule demonstrated proof of concept in promoting wakefulness in narcolepsy patients, and an oral version (TAK-994) was planned (with a targeted launch in 2024) but discontinued due to an undisclosed safety signal.  Hit-Finding Strategy. The OX2R-selective starting point (compound 2, EC50 = 570…