title: Exploiting the Chromone Scaffold for the Development of Inhibitors of Corticosteroid Biosynthesis.
abstract: The inhibition of corticosteroid biosynthesis could be considered as an emerging strategy to reduce their abnormally high levels, and in this framework CYP11B1 and CYP11B2 represent the most promising targets. In continuing our studies on flavonoid-like scaffolds as privileged structures in medicinal chemistry, in this paper we describe a small library of pyridyl- and imidazolylmethylchromones as potential inhibitors of these enzymes. Testing results proved that position 3 of the chromone scaffold is the most favorable for the introduction of the heme-coordinating heterocycles and, among them, the 4-imidazolyl moiety is the most convenient for the interaction with the heme iron of the selected cytochromes. A low nanomolar inhibitor of CYP11B1 (5c) was obtained, endowed with reasonable selectivity toward CYP11B2 and able to better discriminate with respect to CYP17 and CYP19.
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro, 6, I-40126 Bologna, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gobbi
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Universitätscampus E8 1, 66123 Saarbrücken, Germany.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Universitätscampus E8 1, 66123 Saarbrücken, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Zimmer
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Universitätscampus E8 1, 66123 Saarbrücken, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro, 6, I-40126 Bologna, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Belluti
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro, 6, I-40126 Bologna, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Rampa
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Universitätscampus E8 1, 66123 Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro, 6, I-40126 Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisi
mesh_terms: D000305:Adrenal Cortex Hormones / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D000818:Animals; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D054852:Small Molecule Libraries; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000305:Adrenal Cortex Hormones; D047072:Aromatase Inhibitors; D002867:Chromones; D065607:Cytochrome P-450 Enzyme Inhibitors; D006571:Heterocyclic Compounds; D011725:Pyridines; D054852:Small Molecule Libraries; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase