Catechol O-methyltransferase
(COMT) metabolizes neurotransmitters such as dopamine and is a validated target
for Parkinson’s disease. In theory other diseases could be treated with COMT
inhibitors too, but most of these contain – like dopamine itself – catechol
moieties, and thus have lousy pharmacokinetics and poor brain penetration.
Catechols in general are best avoided, and in a recent paper in J. Med. Chem. María Sarmiento and
colleagues at Roche have found an alternate scaffold.
COMT is a magnesium-dependent enzyme, and the catechol binds
to the magnesium ion. The researchers decided to target the pocket that binds
the cofactor, S-adenosyl-L-methionine
(SAM). They screened 6000 rule-of-three compliant fragments at 200 µM using
surface plasmon resonance (SPR). First they examined wild-type enzyme in the
absence of magnesium and SAM, and they also counter-screened against six
variants containing mutations in the SAM binding site to exclude fragments that
bound elsewhere. Even after this specificity profiling 600 hits remained. Dose-response
curves whittled the number down to 200, all of which were examined using
ligand-detected (CPMG) NMR. Hits from CPMG NMR were further studied using protein-detected
(1H/15N HSQC) NMR. Finally, all 600 of the hits from the
initial SPR screen/counter-screen assays were tested in an enzymatic assay. Only
four fragments made it through all of these filters, three of which were
pyrazoles such as compound 1.
Two years ago Teddy highlighted a paper from Takeda also
focused on COMT, and there too pyrazoles predominated – an observation that
didn’t escape the Roche researchers. In fact, compound 1 in the current paper
is almost identical to compound 5 in the Takeda paper. Substructure searching and
screening led to compound 4, which is
identical to compound 7 in the Takeda paper. Whether COMT is really this choosy
when it comes to fragment hits, or whether this reflects similarities in
fragment libraries remains an open question.
But happily there’s more. The researchers used an iterative
structure-guided fragment-growing approach to improve affinity. This ultimately
resulted in compound 24, which is competitive with SAM and has mid-nanomolar
activity. The solubility could be improved, and no other biological
data are presented, but at least this paper demonstrates that it is possible to find potent
inhibitors of COMT that are not phenols or catechols.
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