Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors

ACS Med Chem Lett. 2013 Oct 17;4(12):1203-7. doi: 10.1021/ml400324c.

Erik L Meredith ¹, Gary Ksander ¹, Lauren G Monovich ¹, Julien P N Papillon ¹, Qian Liu ¹, Karl Miranda ¹, Patrick Morris ¹, Chang Rao ¹, Robin Burgis ¹, Michael Capparelli ¹, Qi-Ying Hu ¹, Alok Singh ¹, Dean F Rigel ², Arco Y Jeng ², Michael Beil ², Fumin Fu ², Chii-Whei Hu ², Daniel LaSala ²

Affiliations

1 Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
2 Novartis Pharmaceuticals Corporation , East Hanover, New Jersey 07936, United States.

PMID: 24900631 DOI: 10.1021/ml400324c

Abstract

Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome.

Keywords

CYP11B1; CYP11B2; Cushing’s syndrome; Inhibitor; aldosterone; aldosterone synthase; cortisol; enzyme; hypertension.

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