Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2

It
is necessary for aldosterone synthase (CYP11B2) inhibitors to
have both high potency and high selectivity over 11β-hydroxylase
(CYP11B1), a critical enzyme for cortisol synthesis. Previous studies
have reported a number of CYP11B2 inhibitors, most of which have an
imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2;
however, highly selective inhibitors of human CYP11B2 are still needed.
To expand the selectivity in humans, we explored alternative templates
and found that pyrazoles were suitable templates for CYP11B2 inhibitors.
Investigation of pyrazoles, especially N-alkyl pyrazoles,
as a new template to coordinate the heme-iron motif led to a potent
and highly selective CYP11B2 inhibitor 28 with an aldosterone-lowering
effect at 1 mg/kg dosing in cynomolgus monkeys.