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Discovery and in vivo evaluation of potent dual CYP11B2 (aldosterone synthase) and CYP11B1 inhibitors

Meredith, Erik and Burgis, Robin and Beil, Michael and Capparelli, Michael and Fu, Fumin and Hu, Chii-Whei and Hu, Qi-Ying and Jeng, Arco and Ksander, Gary and Lasala, Daniel and Liu, Qian and Miranda, Karl and Monovich, Lauren and Morris, Patrick and Papillon, Julien and Rao, Chang and Rigel, Dean and Singh, Alok (2013) Discovery and in vivo evaluation of potent dual CYP11B2 (aldosterone synthase) and CYP11B1 inhibitors. ACS Medicinal Chemistry Letters.

Abstract

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.

Item Type: Article
Additional Information: PLEASE READ THE ACCOMPANYING DOCUMENT DETAILING WHAT HAS ALREADY BEEN DISCLOSED EXTERNALLY REGARDING LCI699. This work details the med chem discovery of LCI699 which is in clinical trials for hypertension and cushing's syndrome. The structure of LCI699 has already been disclosed to the public and portions of this work, including, some aspects of both the aldosterone and corticosterone in vivo models has been or is in the process of being published (i.e. already approved for external release).
Keywords: inhibitor, CYP11B2, aldosterone synthase, aldosterone, hypertension, enzyme, CYP11B1, Cushing’s syndrome, cortisol
Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8729

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