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

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.

• Authors: Erik L Meredith, Gary Ksander, Lauren G Monovich, Julien P N Papillon, Qian Liu, Karl Miranda, Patrick Morris, Chang Rao, Robin Burgis, Michael Capparelli, Qi-Ying Hu, Alok Singh, Dean F Rigel, Arco Y Jeng, Michael Beil, Fumin Fu, Chii-Whei Hu, Daniel LaSala
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 4 Issue 12 Pg. 1203-7 (Dec 12 2013) ISSN: 1948-5875 [Print] United States
• PMID: 24900631 (Publication Type: Journal Article)