Substituted phenyl as a steroid A-ring mimetic: providing agonist activity to a class of arylsulfonamide nonsteroidal glucocorticoid ligands.
A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors.
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. Electronic address: darren.disalvo@boehringer-ingelheim.com.
Darren
D
DiSalvo
Daniel
D
Kuzmich
Jörg
J
Bentzien
John
J
Regan
Alison
A
Kukulka
Tazmeen
T
Fadra-Khan
Richard
R
Nelson
Christian
C
Harcken
David
D
Thomson
Gerald
G
Nabozny
D001665:Binding Sites; D005938:Glucocorticoids / Q000737:chemistry; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D013256:Steroids / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid; D013256:Steroids; D013449:Sulfonamides
Arylsulfonamide; Glucocorticoid receptor; Glucocorticoid receptor agonist; Glucocorticoids; Mineralocorticoid receptor; Nuclear hormone receptor; Progesterone receptor