Selective aldosterone synthase inhibitors reduce aldosterone formation in vitro and in vivo.
Aldosterone plays a crucial role in salt and water homeostasis but in case of pathologically increased plasma aldosterone levels it is also involved in the development and the progression of severe cardiovascular diseases like heart failure and myocardial fibrosis. For the treatment of these diseases we propose inhibition of the aldosterone forming enzyme CYP11B2 as a new pharmacological strategy. We recently developed in vitro highly potent and selective inhibitors of human CYP11B2, but the evidence of their in vivo activity is still missing. For this purpose, rat aldosterone synthase gene was cloned and expressed in V79MZ cells to establish a new screening assay for the identification of "rat-active" substances. Compound 7 from the class of heteroaryl substituted 3,4-dihydro-1H-quinolin-2-ones showed a moderate inhibitory effect (65% at 2 microM) on rat CYP11B2 in vitro. Furthermore, it diminished the conversion of deoxycorticosterone to aldosterone in rat adrenals and significantly reduced plasma aldosterone levels in vivo.
Ries
Christina
C
Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany.
Lucas
Simon
S
Heim
Ralf
R
Birk
Barbara
B
Hartmann
Rolf W
RW
D000311:Adrenal Glands / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis* / Q000097:blood; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D015363:Quinolones; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D019405:Cytochrome P-450 CYP11B2