The discovery of potent inhibitors of aldosterone synthase that exhibit selectivity over 11-b-hydroxylase Christopher M. Adams a, * , Chii-Whei Hu b , Arco Y. Jeng b , Rajeshri Karki a , Gary Ksander a , Dan LaSala b , Jennifer Leung-Chu b , Guiqing Liang c , Qian Liu a , Erik Meredith a , Chang Rao a , Dean F. Rigel b , Jie Shi a , Sherri Smith c , Clayton Springer a , Chun Zhang a a Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Ave., Cambridge, MA 02139, USA b Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936, USA c Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, 250 Massachusetts Ave., Cambridge, MA 02139, USA article info Article history: Received 11 April 2010 Revised 12 June 2010 Accepted 15 June 2010 Available online 19 June 2010 Keywords: CYP11B2 Aldosterone CYP11B1 Aldosterone synthase inhibitor Hypertension. abstract Aldosterone, the final component of the renin–angiotensin–aldosterone system, plays an important role in the pathophysiology of hypertension and congestive heart failure. Aldosterone synthase (CYP11B2) catalyzes the last three steps of aldosterone biosynthesis, and as such appears to be a target for the treat- ment of these disorders. A sulfonamide–imidazole scaffold has proven to be a potent inhibitor of CYP11B2. Furthermore, this scaffold can achieve high levels of selectivity for CYP11B2 over CYP11B1, a key enzyme in the biosynthesis of cortisol. Ó 2010 Elsevier Ltd. All rights reserved. The renin–angiotensin–aldosterone system (RAAS) is a key reg- ulator of blood pressure and extracellular volume. Aldosterone, the final component of the RAAS, is a potent mineralocorticoid. Ele- vated aldosterone levels play an important role in the pathophys- iology of hypertension and congestive heart failure. 1 As such, aldosterone has attracted much attention from both the pharma- ceutical and clinical communities. Until recently, the majority of this effort has focused on mineralocorticoid receptor (MR) antago- nists, such as spironolactone and eplerenone. 2,3 However, current evidence indicates that the deleterious effects of elevated aldoste- rone levels are not solely mediated by the MR and that non-geno- mic effects may play a critical role. 4,5 Therefore, directly inhibiting the synthesis of aldosterone may prove advantageous. 6 The final three steps of aldosterone biosynthesis are catalyzed by a single cytochrome P450 enzyme, CYP11B2, which is expressed in zona glomerulosa cells of the adrenal gland. 7 Importantly, fadroz- ole, an inhibitor of CYP11B2, has been shown to reduce aldosterone levels in humans. 8 Fadrozole was initially developed as an aroma- tase (CYP19) inhibitor, but it was later discovered that the R-enan- tiomer of fadrozole (FAD286, Fig. 1) is a potent aldosterone synthase inhibitor. 9 Subsequent studies have shown that FAD286 is also an inhibitor of 11-b-hydroxylase (CYP11B1). CYP11B1 is also expressed in the adrenal gland and catalyzes the last step in the biosynthesis of cor- tisol, the primary glucocorticoid. 7 Cortisol mediates the stress re- sponse affecting energy mobilization and the immune system. Therefore, a selective CYP11B2 inhibitor may be desirable. FAD286 exhibits IC 50 values of 1.6 and 9.9 nM in recombinant hu- man CYP11B2 and CYP11B1 enzyme assays, respectively. 10 This small degree of selectivity is not surprising, considering that the amino acid sequences of these two enzymes are 95% identical in the coding regions. 11 Homology models of the two enzymes 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.06.086 * Corresponding author. Tel.: +1 617 871 7724. E-mail address: christopherM.adams@novartis.com (C.M. Adams). N N CN N N N O CN FAD286 1 Figure 1. The R-enantiomer of fadrozole (FAD286) and a representative analog from the lactam series (1). Bioorganic & Medicinal Chemistry Letters 20 (2010) 4324–4327 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl