Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase.

2.50
Hdl Handle:
http://hdl.handle.net/10033/344570
Title:
Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase.
Authors:
Stefanachi, Angela; Hanke, Nina; Pisani, Leonardo; Leonetti, Francesco; Nicolotti, Orazio; Catto, Marco; Cellamare, Saverio; Hartmann, Rolf W; Carotti, Angelo
Abstract:
Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration).
Affiliation:
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), PO Box 15 11 50, D-66041 Saarbrücken, Germany.
Citation:
Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase. 2015, 89:106-14 Eur J Med Chem
Journal:
European journal of medicinal chemistry
Issue Date:
7-Jan-2015
URI:
http://hdl.handle.net/10033/344570
DOI:
10.1016/j.ejmech.2014.10.021
PubMed ID:
25462231
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.authorStefanachi, Angelaen
dc.contributor.authorHanke, Ninaen
dc.contributor.authorPisani, Leonardoen
dc.contributor.authorLeonetti, Francescoen
dc.contributor.authorNicolotti, Orazioen
dc.contributor.authorCatto, Marcoen
dc.contributor.authorCellamare, Saverioen
dc.contributor.authorHartmann, Rolf Wen
dc.contributor.authorCarotti, Angeloen
dc.date.accessioned2015-02-18T13:39:43Z-
dc.date.available2015-02-18T13:39:43Z-
dc.date.issued2015-01-07-
dc.identifier.citationDiscovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase. 2015, 89:106-14 Eur J Med Chemen
dc.identifier.issn1768-3254-
dc.identifier.pmid25462231-
dc.identifier.doi10.1016/j.ejmech.2014.10.021-
dc.identifier.urihttp://hdl.handle.net/10033/344570-
dc.description.abstractDiseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration).en
dc.language.isoenen
dc.titleDiscovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Institute for Pharmaceutical Research Saarland (HIPS), PO Box 15 11 50, D-66041 Saarbrücken, Germany.en
dc.identifier.journalEuropean journal of medicinal chemistryen

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