The name herpes makes most people
think of painful ulcers in the mouth, or worse. But herpesviruses are actually
a family of viruses that can also cause chicken pox, mononucleosis, and other
diseases. Some 95% of adults are infected by at least one type of herpesvirus, and
these can become deadly if people become immunocompromised, such as during an
organ transplant. A drug that would inhibit all forms of herpesviruses would be
useful, and the first steps are described in a recent ACS Med. Chem. Lett.
paper by Michael Plotkin and colleagues at Merck.
The details of the primary screen
are sparse, though the researchers did say they physically screened more than
100,000 compounds to identify molecules such as compound 5, a modest inhibitor
of the DNA polymerases from both cytomegalovirus (CMV) and varicella zoster virus
(VZV). (For most compounds the paper reports biochemical activity towards both
of these polymerases as well as antiviral activity for CMV, VZV, herpes simplex
virus 1 (HSV-1), and HSV-2, but for simplicity I’ll only show data for CMV
here. The compounds generally have comparable activity towards different
viruses.)
Hydrogen bond acceptors such as
the ketone in compound 5 were found to be essential for activity, and exploring
a variety of analogs led to compound 12, which in addition to submicromolar
biochemical activity against the DNA polymerases also showed antiviral activity
against CMV and other herpesviruses.
The paper goes into considerable
detail on the lead optimization. The (S) enantiomer of compound 12 was an order
of magnitude more potent than the (R) enantiomer. Modifications made to both of
the phenyl rings ultimately led to compound 44, with low nanomolar
biochemical activity against the polymerases and sub-micromolar antiviral
activity against CMV, VZV, HSV-1, and HSV-2. Importantly, the researchers note
that they did not have crystal structures during optimization, a useful reminder
that structural information is not always necessary.
Compound 44 had modest oral
bioavailability in rodents, but closely related compound 42 containing a
trifluoromethyl group in place of the bromine was better, albeit with slightly lower biochemical potency. This molecule led to
high survival rates in mice when dosed either before or after being exposed
to HSV-1. In separate studies, the compound reduced CMV viral load. For both
HSV-1 and CMV compound 42 compared favorably to acyclovir and ganciclovir, two commonly
used drugs.
Although there is still some way
to go to a drug, the researchers end by promising to describe “further progress
of this series.” I look forward to reading about this.
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