The discovery of potent inhibitors of aldosterone synthase that exhibit selectivity over 11-beta-hydroxylase.
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.
Adams
Christopher M
CM
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. christopherM.adams@novartis.com
Hu
Chii-Whei
CW
Jeng
Arco Y
AY
Karki
Rajeshri
R
Ksander
Gary
G
Lasala
Dan
D
Leung-Chu
Jennifer
J
Liang
Guiqing
G
Liu
Qian
Q
Meredith
Erik
E
Rao
Chang
C
Rigel
Dean F
DF
Shi
Jie
J
Smith
Sherri
S
Springer
Clayton
C
Zhang
Chun
C
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
D004791:Enzyme Inhibitors; D007093:Imidazoles; D013449:Sulfonamides; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase