Optimization of the First Selective Steroid-11β-hydroxylase (CYP11B1) Inhibitors for the Treatment of Cortisol Dependent Diseases

CYP11B1 is the key enzyme in cortisol biosynthesis, and its inhibition with selective compounds is a promising strategy for the treatment of diseases associated with elevated cortisol levels, such as Cushing's syndrome or metabolic disease. Expanding on a previous study from our group resulting in the first potent and rather selective inhibitor described so far (1, IC50 = 152 nM), we herein describe further optimizations of the imidazolylmethyl pyridine core. Five compounds among the 42 substances synthesized showed IC50 values below 50 nM. Most interesting was the naphth-1-yl compound 23 (IC50 = 42 nM), showing a 49-fold selectivity toward the highly homologous CYP11B2 (1: 18-fold) as well as selectivity toward the androgen and estrogen forming enzymes CYP17 and CYP19, respectively.