Discovery of N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects

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 8.

Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2)

“…Some other selective AS inhibitors have recently been reported, but the only one to date tested in humans did not reduce plasma aldosterone by >70%, even at high doses. 23 Previous AS inhibitors to enter clinical development were LCI699 and fadrozole. Of these, LCI699 has been repurposed for the treatment of Cushing disease, where excess of cortisol is the cardinal clinical feature, 19 and fadrozole is an aromatase inhibitor used for the treatment of breast cancer.…”

Development of Highly Selective Pyrimidine-Based Aldosterone Synthase (CYP11B2) Inhibitors

“…8 However, several recent reports detail significant progress in the development of selective inhibitors, 12−15 including the identification of highly selective clinical candidates LFF269 and RO-6836191. 16,17 Our approach to the design of highly selective metalloenzyme inhibitors focuses on the optimization of the inhibitor metal binding group (MBG)−enzyme metal ion interaction and has been successfully employed for the development of highly selective inhibitors of related cytochrome P450 enzymes, fungal CYP51 and CYP17. 18,19 Recognition that overly potent MBGs (pyridines and imidazoles for heme-iron) exert potent off-target activities causing side-effects, led to consideration of less metal-avid MBGs to improve selectivity, and provide an opportunity for an improved therapeutic window.…”

Drifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1

“…These enzyme isoforms are mainly expressed in the adrenal cortex, CYP11B1 in the zona fasciculata and CYP11B2 in the zona glomerulosa, and share a degree of sequence homology up to 93%, making the design of specific and selective inhibitors particularly challenging. In recent years, highly selective CYP11B2 inhibitors have been reported [5][6][7][8], characterized by a significant structural scaffold variance, still bearing the key features for an efficient cytochrome inhibition, such as nitrogen-containing heterocyclic functions (pyridine or imidazole), able to interact with the hemeiron of the active site.…”