Discovery of a subnanomolar and selective spirocyclic agonist of the glucocorticoid receptor.

Autor: Badarau E; Univ. Bordeaux, European Institute of Chemistry and Biology (IECB), 2 Rue Robert Escarpit, 33607, Pessac, France; Univ. Bordeaux, Institute of Chemistry & Biology of Membranes & Nano-objects (CBMN), Allée Geoffroy Saint Hilaire, Bât B14, 33600, Pessac, France., Robert F; Univ. Bordeaux, Institute of Molecular Sciences (ISM), Bâtiment A12, 351 cours de la Libération, 33405, TALENCE Cedex, France., Massip S; Univ. Bordeaux, European Institute of Chemistry and Biology (IECB), 2 Rue Robert Escarpit, 33607, Pessac, France., Jakob F; Grunenthal GmbH, Zieglerstr. 6, 52078, Aachen, Germany., Lucas S; Grunenthal GmbH, Zieglerstr. 6, 52078, Aachen, Germany., Friebe D; Grunenthal GmbH, Zieglerstr. 6, 52078, Aachen, Germany., Hennen S; Grunenthal GmbH, Zieglerstr. 6, 52078, Aachen, Germany., Frormann S; Grunenthal GmbH, Zieglerstr. 6, 52078, Aachen, Germany., Ghosez L; Univ. Bordeaux, European Institute of Chemistry and Biology (IECB), 2 Rue Robert Escarpit, 33607, Pessac, France. Electronic address: l.ghosez@iecb.u-bordeaux.fr.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2019 Jan 01; Vol. 161, pp. 354-363. Date of Electronic Publication: 2018 Oct 15.
DOI: 10.1016/j.ejmech.2018.10.032
Abstrakt: Pure diastereomeric spirocyclic analogs of fluorocortivazol were conveniently prepared by a short and efficient synthetic sequence recently developed in our laboratory. The structures and conformations of several key products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. Biological evaluation led to the identification of a highly potent hGR agonist with excellent anti-inflammatory effects in the subnanomolar range. All tested compounds from this series were also selective versus the progesterone receptor.
(Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: