Identification of 4-(4-nitro-2-phenethoxyphenyl)pyridine as a promising new lead for discovering inhibitors of both human and rat 11β-Hydroxylase.

2.50
Hdl Handle:
http://hdl.handle.net/10033/556203
Title:
Identification of 4-(4-nitro-2-phenethoxyphenyl)pyridine as a promising new lead for discovering inhibitors of both human and rat 11β-Hydroxylase.
Authors:
Hu, Qingzhong; Kunde, Jessica; Hanke, Nina; Hartmann, Rolf W
Abstract:
The inhibition of 11β-hydroxylase is a promising strategy for the treatment of Cushing's syndrome, in particular for the recurrent and subclinical cases. To achieve proof of concept in rats, efforts were paid to identify novel lead compounds inhibiting both human and rat CYP11B1. Modifications on a potent promiscuous inhibitor of hCYP11B1, hCYP11B2 and hCYP19 (compound IV) that exhibited moderate rCYP11B1 inhibition led to compound 8 as a new promising lead compound. Significant improvements compared to starting point IV were achieved regarding inhibitory potency against both human and rat CYP11B1 (IC50 values of 2 and 163 nM, respectively) as well as selectivity over hCYP19 (IC50 = 1900 nM). Accordingly, compound 8 was around 7- and 28-fold more potent than metyrapone regarding the inhibition of human and rat CYP11B1 and exhibited a comparable selectivity over hCYP11B2 (SF of 3.5 vs 4.9). With further optimizations on this new lead compound 8, drug candidates with satisfying profiles are expected to be discovered.
Affiliation:
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.
Citation:
Identification of 4-(4-nitro-2-phenethoxyphenyl)pyridine as a promising new lead for discovering inhibitors of both human and rat 11β-Hydroxylase. 2015, 96:139-50 Eur J Med Chem
Journal:
European journal of medicinal chemistry
Issue Date:
26-May-2015
URI:
http://hdl.handle.net/10033/556203
DOI:
10.1016/j.ejmech.2015.04.013
PubMed ID:
25874338
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.authorHu, Qingzhongen
dc.contributor.authorKunde, Jessicaen
dc.contributor.authorHanke, Ninaen
dc.contributor.authorHartmann, Rolf Wen
dc.date.accessioned2015-06-03T12:52:31Zen
dc.date.available2015-06-03T12:52:31Zen
dc.date.issued2015-05-26en
dc.identifier.citationIdentification of 4-(4-nitro-2-phenethoxyphenyl)pyridine as a promising new lead for discovering inhibitors of both human and rat 11β-Hydroxylase. 2015, 96:139-50 Eur J Med Chemen
dc.identifier.issn1768-3254en
dc.identifier.pmid25874338en
dc.identifier.doi10.1016/j.ejmech.2015.04.013en
dc.identifier.urihttp://hdl.handle.net/10033/556203en
dc.description.abstractThe inhibition of 11β-hydroxylase is a promising strategy for the treatment of Cushing's syndrome, in particular for the recurrent and subclinical cases. To achieve proof of concept in rats, efforts were paid to identify novel lead compounds inhibiting both human and rat CYP11B1. Modifications on a potent promiscuous inhibitor of hCYP11B1, hCYP11B2 and hCYP19 (compound IV) that exhibited moderate rCYP11B1 inhibition led to compound 8 as a new promising lead compound. Significant improvements compared to starting point IV were achieved regarding inhibitory potency against both human and rat CYP11B1 (IC50 values of 2 and 163 nM, respectively) as well as selectivity over hCYP19 (IC50 = 1900 nM). Accordingly, compound 8 was around 7- and 28-fold more potent than metyrapone regarding the inhibition of human and rat CYP11B1 and exhibited a comparable selectivity over hCYP11B2 (SF of 3.5 vs 4.9). With further optimizations on this new lead compound 8, drug candidates with satisfying profiles are expected to be discovered.en
dc.language.isoenen
dc.titleIdentification of 4-(4-nitro-2-phenethoxyphenyl)pyridine as a promising new lead for discovering inhibitors of both human and rat 11β-Hydroxylase.en
dc.typeArticleen
dc.contributor.departmentPharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.en
dc.identifier.journalEuropean journal of medicinal chemistryen
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