How Does This Thing Get in the Brain??

At AAPS 2022, I hosted a symposium where Ovoca Bio plc’s Head of Research, Mikhail Lomonosov told us about orenetide. Orenetide is an internationally approved peptide drug for hypoactive sexual desire disorder (HSDD) (think Viagra for women). It appears to work within a few weeks in humans with a solid safety profile – Mikhail noted that one of the challenges in securing US approval was they couldn’t dose the intranasal drug high enough in animals to satisfy the FDA! It turns out, mice have very small nasal cavities.

orenetide chemical structure ovoca bio hsdd

As a chemist, this one raised eyebrows. How the heck does this thing get into the brain? As a highly polar drug with four charged motifs (three amines, one acid) and a MW of nearly 600, it’s not winning any CNS drug property awards.

There are a few hypotheses in the literature for nose-to-brain drugs. For blood-brain-barrier-penetrant small molecules, they may be absorbed in the blood and then pass to the brain, which likely doesn’t apply here. It’s been proposed that drugs can also accumulate in the olfactory bulb, and migrate to the brain from there. Mikhail’s Ovoca team tested this by directly injecting the drug into the olfactory bulb in rodents, but didn’t see any drug effects, ruling that out.

A third hypothesis is that the drug rides along the trigeminal nerve either intraneuronally or perivascularly to the brain stem, and then the brain. Ruling out the other two options, this seems to be the most likely path. Mikhail noted that this area has been actively debated in the literature for decades, and their results are rare evidence supporting non-olfactory bulb-mediated drug delivery.

So, if you’re not actively reading The Journal of Sexual Medicine, attending AAPS sessions, or getting updates through Drug Hunter, you might be missing out on updates in drug discovery 😉

Other great talks in the session included a discussion of Merck’s NaV1.7 program by Merck Principal Scientist Jeanine Ballard and Repare’s atropisomeric PKMYT1 inhibitor RP-6036 by DMPK Director Robert Papp

Jeanine told us to watch out for soon-to-be published data on Merck clinical IV candidate MK-2075, which saw adverse events in the clinic related to baroreceptor reflex which may be NaV1.7-mediated. 

Robert noted an ununsual phenomenon with their phenol molecules, in which one atropisomer had dramatically greater in-vivo clearance than the other, which was suspected to be due to differential glucuronidation activity on the atropisomeric phenols.

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