1. Drifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1
- Author
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Rolf W. Hartmann, Alessandra Bisi, Federica Belluti, Angela Rampa, Christina Zimmer, Silvia Gobbi, Qingzhong Hu, HIPS, Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany., Gobbi, Silvia, Qingzhong, Hu, Zimmer, Christina, Belluti, Federica, Rampa, Angela, Hartmann, Rolf W., and Bisi, Alessandra
- Subjects
0301 basic medicine ,Gene isoform ,CYP11B2 (aldosterone synthase) ,Inhibitor ,Stereochemistry ,Xanthones ,Substituent ,Xanthone ,01 natural sciences ,Molecular Docking Simulation ,CYP11B1 (11-β-hydroxylase) ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Cytochrome ,Drug Discovery ,Humans ,Enzyme Inhibitor ,Structure–activity relationship ,Enzyme Inhibitors ,Imidazole ,Heme ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Imidazoles ,General Medicine ,0104 chemical sciences ,030104 developmental biology ,chemistry ,Biochemistry ,Docking (molecular) ,Steroid 11-beta-Hydroxylase ,Pharmacophore ,Human - Abstract
An abnormal increase in glucocorticoid levels is responsible for pathological disorders affecting different organs and systems, and the selective inhibition of appropriate steroidogenic enzymes represents a validated strategy to restore their physiological levels. In continuing our studies on CYP11B inhibitors, in this paper a small series of 6-substituted 3-imidazolylmethylxanthones was designed and synthesized, according to the data acquired from previously reported series of derivatives and from a purposely-performed docking study. The new compounds proved to be potent inhibitors of CYP11B isoforms, being effective on CYP11B1 in the low nanomolar range and improving selectivity with respect to CYP11B2, compared to previously reported related compounds. These data further confirmed that a suitable mutual arrangement of the imidazolylmethyl pharmacophore and a properly selected substituent on the xanthone core allows a fine tuning of the activity towards the different CYPs and further corroborate the role of the xanthone scaffold as a privileged structure in this field.
- Published
- 2017
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