Fragments in the clinic: verubecestat

Of all the fragment-derived drugs in the clinic, perhaps none is so closely watched as verubecestat (MK-8931), Merck’s BACE1 inhibitor in phase 3 clinical trials for Alzheimer’s disease (AD). With tens of millions of cases worldwide, few other diseases in the developed world are as simultaneously widespread, expensive, and terrifying. And despite billions of dollars thrown at the problem, failure rates are nearly 100%. A recent open-access paper by Jack Scott, Andrew Stamford, and collaborators at Merck and AMRI in J. Med. Chem. provides an excellent overview of this latest contender.

We first wrote about Merck’s BACE1 program almost exactly seven years ago, describing how an NMR screen had provided a weak hit that was optimized to nanomolar inhibitors of the enzyme. However, the molecules could fairly be called molecularly obese. This led the researchers to trim back portions of the molecule, losing affinity but gaining cell-based activity and permeability, ultimately resulting in compound 5 (below) – which is itself a fragment. The current paper describes the optimization of this molecule.

Growing compound 5 and expanding the heterocyclic ring led to compound 7, with low nanomolar biochemical and cell-based activity. The iminopyrimidinone core was becoming increasingly crowded from an intellectual-property standpoint, so the researchers replaced this with the iminothiadiazinane dioxide in compound 9, which modeling suggested should have a similar conformation – a result confirmed by crystallography. However, the alkyne moiety appeared to be metabolically unstable. More importantly, compound 9 was only 47-fold selective against the enzyme cathepsin D (CatD). An earlier Lilly BACE1 inhibitor with a similarly modest selectivity had failed due to toxicity possibly associated with CatD, and the researchers were keen to avoid a similar fate. This led them through additional rounds of optimization, ultimately resulting in verubecestat.

In addition to having low nanomolar biochemical and cell-based activity against BACE1, verubecestat is >45,000-fold selective against CatD, has good pharmacokinetics, is orally bioavailable, and is highly soluble (1.6 mM!) It does not inhibit CYP enzymes and has good brain penetration. Rule-checkers might be surprised at this later point given the high calculated polar surface area (115 Ų), a fact the researchers attribute to an intramolecular hydrogen bond between the amide and the pyridine nitrogen, effectively masking these moieties from the point of view of membranes.

A couple potential liabilities stood out. First, one metabolite is an aniline, and anilines can be mutagenic. Reassuringly, an Ames test on this particular aniline showed no mutagenicity. Also, verubecestat is a 2.2 µM hERG inhibitor, and inhibitors of this channel can cause cardiac arrhythmias. However, this concentration is significantly higher than the highest expected in humans, and studies in primates revealed no safety issues. All of which is a useful reminder that, in our business, rules are at most guidelines, and data is king.

The paper also includes some human data demonstrating that the compound is safe at doses up to 550 mg (!) and causes a dose-dependent reduction in β-amyloid levels. With the results of the first Phase 3 trial expected later this year, we could know soon whether this is a billion dollar molecule or yet another massively expensive failure. If the former, verubecestat could be one of those transformational advances in drug discovery that comes along once in a generation. But even if fails, this is the clearest test yet of the amyloid hypothesis. And fragments made it possible.