A year into the COVID-19 pandemic
more than 2.3 million people have died, with deaths in the US approaching
500,000. These are staggering numbers, and the scientific community has rapidly
responded. Amidst this disaster, it is easy to lose sight of longstanding, even
more deadly threats, such as heart disease.
A leading cause of metabolic
disease is overconsumption of fructose. Because it is sweeter than other natural
sugars and cheap to produce, fructose is widely used in processed foods. Fructose
is not subject to the negative feedback regulation of other sugars, and overconsumption
has been linked to nonalcoholic fatty liver disease (NAFLD), insulin
resistance, and cardiovascular disease. The first step in fructose metabolism
is mediated by the enzyme ketohexokinase (KHK), so blocking it seems like a
reasonable approach.
More than three years ago we
highlighted a paper from Pfizer describing the fragment-based effort which led
to compound 1, an inhibitor of KHK. That post ended by noting that there was “still
some way to go” to reach a drug. A paper published late last year in
J. Med. Chem. by Kentaro Futatsugi and colleagues from Pfizer describes the
journey to the clinic.
Compound 1 was well-suited to SAR
by parallel synthesis, and a variety of replacements for the methylpyrrolidine
(on top) led to compound 3. Although this molecule had similar affinity as
compound 1, a crystal structure revealed that it had shifted its binding mode
such that the other pyrrolidine ring was pointing towards an important arginine
residue. Exploring a diverse range of replacements led to compound 4, with improved
affinity driven in part due to interactions between the hydroxyl and the
arginine side chain. Replacing this hydroxyl with a carboxylic acid led at last
to a low nanomolar lead.
Compound 6 was unstable when
incubated with human hepatocytes, and various studies revealed that glucuronidation
at the remaining hydroxyl was responsible. Removing the hydroxyl and lowering
lipophilicity by removing the nitrile ultimately led to PF-06835919. This compound
is potent, orally bioavailable, and clean in a variety of off-target assays.
This is a beautiful example of lead
optimization guided by structure with a keen focus on molecular and
pharmaceutical properties. The initial fragments are difficult to discern in
the final molecule, which is not a bad thing: the whole point of fragment-based
discovery is giving multiple options for creative medicinal chemistry. In
contrast to last week’s post, crystallography was essential for the program; it
also benefited from the applied serendipity of parallel synthesis.
Often these sorts of publications
are the valediction of a halted program, but not here: PF-06835919 is moving forward
in three clinical trials, including a phase 2 trial for NAFLD. Interestingly, the compound
was first dosed in humans in 2016 – a year before the initial paper. This gap
between clinical efforts and publications is a reminder that our list of
fragment-derived clinical compounds will always be incomplete. I look forward
to watching PF-06835919 advance.
No comments:
Post a Comment