TAK-861, currently in Phase-3 is the first-in-class oral orexin agonist from Takeda as an exciting new option for managing Narcolepsy type 1 (NT1). Narcolepsy is a rare chronic neurological disorder where people with deficiency in the neurotransmitter orexin not only feel excessive daytime sleepiness, but they often also experience sudden muscle weakness called cataplexy, fragmented sleep, and sleep paralysis. What makes the journey to TAK-861 really inspirational is the comeback which took two years of hard work from the team at Takeda after tackling severe liver toxicity issues and a trial halt during the development of TAK-994, an earlier direct orexin agonist. Operating at lower dose compared to TAK-994, TAK-861 is more potent and has a very nice pharmacokinetic profile which allows orexin to rise to a normal level during the day, but at night, the levels persist because of the drug's long half-life that mimics the natural fluctuation of orexin A classic MedChem case study that once again elucidates many roles Fluorine can play in a single molecule. And yes, a real inspirational story, reflecting the intense sense of purpose and commitment on part of Takeda and the team lead by Elena Koundourakis towards the patients by staying up all the night for the program to see the light of the day. https://lnkd.in/dHepEG89 https://lnkd.in/dKRjcThD https://lnkd.in/dEBR9NTK
Looks like in TAK-861, fluoro and methyl groups were strategically added compared to TAK-994 to improve the compound’s pharmacokinetic properties and reduce hepatotoxicity. Clever structural adjustment…
🧠 Exceptionally insightful commentary, as always, Gagan Kukreja! It's fascinating how the aminopyrrolidine moiety emerges as a pivotal suspect 🕵️♂️ behind the liver toxicity observed. This immediately brings to mind parallels with pyrrolizidine alkaloids and their well-documented hepatotoxicity/DILI 📚, with senecionine standing out as a particularly notorious example. 💡 Intriguingly, one wonders if a similar trajectory unfolds here — aromatization to pyrrole within the liver, followed by benzylic oxidation at the central fluoro phenylidene moiety 🌀, potentially leading to the formation of reactive intermediates responsible for DILI ⚠️. Introducing a gem-difluoro moiety might block this oxidative aromatization 🔄, potentially averting the hepatotoxicity 🛡️. (scheme h/t Wikicommons)
Fantastic fluorines! The fluorines on the pyrrole are fantastic in that they do more than block metabolic oxidation. They lower the pKa of the sulfonamide to where it can ionize possibly for water solubility but also they accept an intramolecular H-bond from that NH making the molecule less polar and hence more permeable. Maybe they also inductively improve H-bonding to the O atoms and thus enhance potency.
Takeda has been the trailblazer in the orexin-2 receptor agonist field, but it still remains to be seen which of the drugs in development becomes the official first-in-class (approved) and then which becomes the recognized best-in-class (efficacy, safety, tolerability, convenience, and/or broad utility for multiple disease indications). These are truly exciting times for a potential mega-blockbuster novel mechanism of action…
As a person with narcolepsy and a science degree holder, TAK-861 is beautiful on many levels for me. It’s a great comeback story and a novel solution…. And one that could essentially normalize the extremely struggle of myself and other people with narcolepsy.
It's truly inspiring to witness the dedication and hard work that has gone into the development of TAK-861 💪✨. The potential positive impact this could have for those living with Narcolepsy type 1 is exciting 🎉. Kudos to the entire Takeda team for their perseverance and commitment to improving patients' lives! 🙌❤️ #InnovationInHealthcare #Narcolepsy #PatientCare #HealthcareInnovation
So Molecular Sherlock got it right…
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3wCurious about the persistence in the environment of fluorine containing drugs after they have exited the body?