Trifluoromethyl group as a pharmacophore: effect of replacing a CF3 group on binding and agonist activity of a glucocorticoid receptor ligand.

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Betageri R, Zhang Y, Zindell RM, Kuzmich D, Kirrane TM, Bentzien J, Cardozo M, Capolino AJ, Fadra TN, Nelson RM, Paw Z, Shih DT, Shih CK, Zuvela-Jelaska L, Nabozny G, Thomson DS

Trifluoromethyl group as a pharmacophore: effect of replacing a CF3 group on binding and agonist activity of a glucocorticoid receptor ligand.

Bioorg Med Chem Lett. 2005 Nov 1;15(21):4761-9.

PubMed ID

16112571 [ View in PubMed

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Abstract

Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Dexamethasone	Glucocorticoid receptor	EC 50 (nM)	1	N/A	N/A	Details
Mifepristone	Glucocorticoid receptor	EC 50 (nM)	2	N/A	N/A	Details