Exploiting the Chromone Scaffold for the Development of Inhibitors of Corticosteroid Biosynthesis

Silvia Gobbi; Qingzhong Hu; Christina Zimmer; Matthias Engel; Federica Belluti; Angela Rampa; Rolf W Hartmann; Alessandra Bisi

doi:10.1021/acs.jmedchem.5b01609

Exploiting the Chromone Scaffold for the Development of Inhibitors of Corticosteroid Biosynthesis

J Med Chem. 2016 Mar 24;59(6):2468-77. doi: 10.1021/acs.jmedchem.5b01609. Epub 2016 Mar 11.

Authors

Silvia Gobbi¹, Qingzhong Hu², Christina Zimmer², Matthias Engel², Federica Belluti¹, Angela Rampa¹, Rolf W Hartmann², Alessandra Bisi¹

Affiliations

¹ Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro, 6, I-40126 Bologna, Italy.
² Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Universitätscampus E8 1, 66123 Saarbrücken, Germany.

PMID: 26938274
DOI: 10.1021/acs.jmedchem.5b01609

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.

MeSH terms

Adrenal Cortex Hormones / antagonists & inhibitors*
Adrenal Cortex Hormones / biosynthesis*
Animals
Aromatase Inhibitors / chemical synthesis
Aromatase Inhibitors / pharmacology
Cell Survival / drug effects
Chromones / chemical synthesis*
Chromones / chemistry*
Chromones / pharmacology
Cytochrome P-450 CYP11B2 / antagonists & inhibitors
Cytochrome P-450 Enzyme Inhibitors / chemical synthesis*
Cytochrome P-450 Enzyme Inhibitors / pharmacology*
Drug Design
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / pharmacology
Humans
Models, Molecular
Molecular Docking Simulation
Pyridines / chemical synthesis
Pyridines / pharmacology
Rats
Small Molecule Libraries
Steroid 11-beta-Hydroxylase / antagonists & inhibitors
Steroid 17-alpha-Hydroxylase / antagonists & inhibitors
Structure-Activity Relationship
Substrate Specificity

Substances

Adrenal Cortex Hormones
Aromatase Inhibitors
Chromones
Cytochrome P-450 Enzyme Inhibitors
Heterocyclic Compounds
Pyridines
Small Molecule Libraries
Steroid 17-alpha-Hydroxylase
Cytochrome P-450 CYP11B2
Steroid 11-beta-Hydroxylase