Fragments in the clinic: MK-8189

Just over seven years ago Practical Fragments highlighted work out of Merck describing the discovery and optimization of potent, selective inhibitors of phosphodiesterase 10A (PDE10A), a potential target for schizophrenia (see here and here). An open-access paper in the latest issue of J. Med. Chem. by Mark Layton and colleagues tells how these were ultimately advanced to a clinical compound.

 

To recap, a biochemical fragment screen identified the highly ligand-efficient compound 1, which was optimized to the potent compound 2. However, this molecule had poor pharmacokinetics and multiple other liabilities. Further optimization led to Pyp-1, which we noted at the time would make a good chemical probe.

 

The new paper continues SAR around the central ring, in particular to try to reduce lipophilicity. Also, the methyl-pyrazole in Pyp-1 was associated with high clearance in rats, so this substituent was replaced with a methyl-1,3,4-thiadiazole moiety. To cut a long story short, this ultimately led to MK-8189.

 

Not only is MK-8189 a picomolar biochemical inhibitor of PDE10A, it is a low nanomolar inhibitor in cells. Moreover, it shows excellent pharmacokinetics in rats and rhesus monkeys as well as selectivity against various off-targets such as CYPs and hERG. Importantly for a drug intended to reach the brain, the molecule is permeable, not effluxed, and achieves relevant concentrations in the rat striatum after oral dosing. Finally, it decreased psychomotor activity and improved episodic memory in rat models of schizophrenia. With all these positives, MK-8189 has been taken into the clinic.

 

Several lessons emerge from this story. First, as experienced drug hunters will recognize, systematic exploration of multiple positions is important to generate a molecule with the right balance of properties to become an investigational drug. Second, as the researchers note, ligand efficiency was roughly maintained throughout the optimization process. Finally, this publication is a reminder of the long lag that can occur between research and publication. We already mentioned that the first papers describing this series appeared in 2015, but according to ClinicalTrials.gov MK-8189 first entered the clinic a year earlier, in 2014. Our list of fragment-derived clinical compounds will forever be incomplete and out of date. But on a positive note, this means that fragments may be having even more of an impact than the list shows.