Function-regulating pharmacophores in a sulfonamide class of glucocorticoid receptor agonists.
A class of α-methyltryptamine sulfonamide glucocorticoid receptor (GR) modulators was optimized for agonist activity. The design of ligands was aided by molecular modeling, and key function-regulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell based assays. Compound 27 was profiled in vitro and in vivo in models of inflammation. Analogs could be rapidly prepared in a parallel approach from aziridine building blocks.
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. Electronic address: dkuzmich@aol.com.
Daniel
D
Kuzmich
Jörg
J
Bentzien
Raj
R
Betageri
Darren
D
DiSalvo
Tazmeen
T
Fadra-Khan
Christian
C
Harcken
Alison
A
Kukulka
Gerald
G
Nabozny
Richard
R
Nelson
Edward
E
Pack
Donald
D
Souza
David
D
Thomson
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D001665:Binding Sites; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014363:Tryptamines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; D014363:Tryptamines
Arylsulfonamide; Collagen induced arthritis; Glucocorticoid receptor; Glucocorticoids; Inflammation; Mineralocorticoid receptor; Nuclear hormone receptor; Progesterone receptor