discovery of nivasorexant, an orexin-1 receptor antagonist

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link to J. Med. Chem. article:
pubs.acs.org/doi/10.1021/acs....
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This video describes the discovery of nivasorexant, a selective orexin-1 receptor antagonists for the treatment of obsessive compulsive disorders. The content of this video was reported by scientists of Idorsia Pharmaceuticals in Allschwil, Switzerland as a Drug Annotation article in the Journal of Medicinal Chemistry. The discovery project started with an advanced compound from previous research, a dual orexin receptor antagonist with poor selectivity between OX1 and OX2. Selectivity for OX1 was refined through improved understanding of the SAR of the series. Research culminated in a compound that was orally available with good brain exposure and efficacy in a rat model for behavioral disorders. Nivasorexant completed phase I trials but failed to meet its primary endpoint in a phase II trial for eating disorders.
This video was created for academic purposes. The creator of the video has no financial stake in the sponsor of the research described in this video.

[@kuyayan]

Fascinating! Randomly (and happily) suggested this video. I happen to regularly read NIH articles too. Subscribed!!

[@ChemHelpASAP]

Welcome to the channel, and thank you for watching. I try to do a new drug approval or med chem lit article every week (maybe 3/month).

[@AlistairKarim]

Got to this video randomly, simply from my recommended tab. And, actually, it's a hell of a lot interesting. Neurochemistry is alien tech to me, but I've dealt at one point with some disorder concerning the hypothalamus. I would easily bet that even if it's useless for eating disorders, simply having an effective orexin antagonist on the market will find its problem and its client. It's a rather rare receptor to target, only modafinil and derivatives come to mind.

[@ChemHelpASAP]

I'm glad the KZbin algorithm found a match for you. Yes, it does seem to be an uncommon target. I wasn't aware of it before this video.

[@joshyu1124]

I don't remember ever seeing a drug with brain to plasma ratio greater than 1. If this is true, it's incredible.

[@ChemHelpASAP]

My experience with CNS drugs is very limited. Regardless, based on the supplementary information, the brain-to-plasma ratio, the brain concentration (unbound concentration in the brain) is determined through homogenizing brain tissue from the rats and measuring drug concentrations in the brain tissue. It would be interesting to see other concentrations - in muscle, in lung, in adipose, etc. - to see whether this is truly a concentrative effect in the brain or general distribution from the plasma to any tissue. It is remarkable that moving the methyl by one position can make such a large difference in tissue distribution.

[@aaronstevens5960]

First

[@ChemHelpASAP]

and best?

[@aaronstevens5960]

​@@ChemHelpASAPof course

[@andywong1706]

Is there any possibility that you can introduce some prodrug design and synthesis work?