Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase.

2.50
Hdl Handle:
http://hdl.handle.net/10033/346915
Title:
Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase.
Authors:
Grombein, Cornelia M; Hu, Qingzhong; Rau, Sabrina; Zimmer, Christina; Hartmann, Rolf W
Abstract:
Aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 < 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2 μM).
Affiliation:
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Campus C2 3, D-66123 Saarbrücken, Germany.
Citation:
Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase. 2015, 90:788-96 Eur J Med Chem
Journal:
European journal of medicinal chemistry
Issue Date:
27-Jan-2015
URI:
http://hdl.handle.net/10033/346915
DOI:
10.1016/j.ejmech.2014.12.022
PubMed ID:
25528333
Type:
Article
Language:
en
ISSN:
1768-3254
Appears in Collections:
publications of the department drug design and optimization (HIPS]DDOP)

Full metadata record

DC FieldValue Language
dc.contributor.authorGrombein, Cornelia Men
dc.contributor.authorHu, Qingzhongen
dc.contributor.authorRau, Sabrinaen
dc.contributor.authorZimmer, Christinaen
dc.contributor.authorHartmann, Rolf Wen
dc.date.accessioned2015-03-19T15:21:26Zen
dc.date.available2015-03-19T15:21:26Zen
dc.date.issued2015-01-27en
dc.identifier.citationHeteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase. 2015, 90:788-96 Eur J Med Chemen
dc.identifier.issn1768-3254en
dc.identifier.pmid25528333en
dc.identifier.doi10.1016/j.ejmech.2014.12.022en
dc.identifier.urihttp://hdl.handle.net/10033/346915en
dc.description.abstractAldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 < 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2 μM).en
dc.language.isoenen
dc.titleHeteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Institute for Pharmaceutical Research Saarland (HIPS) Campus C2 3, D-66123 Saarbrücken, Germany.en
dc.identifier.journalEuropean journal of medicinal chemistryen

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