Exploiting the Chromone Scaffold for the Development of Inhibitors of Corticosteroid Biosynthesis

The
inhibition of corticosteroid biosynthesis could be considered
as an emerging strategy to reduce their abnormally high levels, and
in this framework CYP11B1 and CYP11B2 represent the most promising
targets. In continuing our studies on flavonoid-like scaffolds as
privileged structures in medicinal chemistry, in this paper we describe
a small library of pyridyl- and imidazolylmethyl­chromones as
potential inhibitors of these enzymes. Testing results proved that
position 3 of the chromone scaffold is the most favorable for the
introduction of the heme-coordinating heterocycles and, among them,
the 4-imidazolyl moiety is the most convenient for the interaction
with the heme iron of the selected cytochromes. A low nanomolar inhibitor
of CYP11B1 (5c) was obtained, endowed with reasonable
selectivity toward CYP11B2 and able to better discriminate with respect
to CYP17 and CYP19.