Discovery of <i>N</i>‑[5-(6-Chloro-3-cyano-1-methyl‑1<i>H</i>‑indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide,
a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human
Subjects
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Abstract
Human
clinical studies conducted with LCI699 established aldosterone
synthase (CYP11B2) inhibition as a promising novel mechanism to lower
arterial blood pressure. However, LCI699’s low CYP11B1/CYP11B2
selectivity resulted in blunting of adrenocorticotropic hormone-stimulated
cortisol secretion. This property of LCI699 prompted its development
in Cushing’s disease, but limited more extensive clinical studies
in hypertensive populations, and provided an impetus for the search
for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the
discovery, pharmacokinetics, and pharmacodynamic data in preclinical
species and human subjects of the selective CYP11B2 inhibitor <b>8</b>