title: The discovery of potent inhibitors of aldosterone synthase that exhibit selectivity over 11-beta-hydroxylase.
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 treatment 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.
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. christopherM.adams@novartis.com
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
authors.forename: Chii-Whei
authors.initials: CW
authors.lastname: Hu
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.forename: Rajeshri
authors.initials: R
authors.lastname: Karki
authors.forename: Gary
authors.initials: G
authors.lastname: Ksander
authors.forename: Dan
authors.initials: D
authors.lastname: Lasala
authors.forename: Jennifer
authors.initials: J
authors.lastname: Leung-Chu
authors.forename: Guiqing
authors.initials: G
authors.lastname: Liang
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Erik
authors.initials: E
authors.lastname: Meredith
authors.forename: Chang
authors.initials: C
authors.lastname: Rao
authors.forename: Dean F
authors.initials: DF
authors.lastname: Rigel
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.forename: Sherri
authors.initials: S
authors.lastname: Smith
authors.forename: Clayton
authors.initials: C
authors.lastname: Springer
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
mesh_terms: D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D013449:Sulfonamides; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase