Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc.
The structure-activity relationships of T0901317 analogs were explored as RORc inverse agonists using the principles of property- and structure-based drug design. An X-ray co-crystal structure of T0901317 and RORc was obtained and provided molecular insight into why T0901317 functioned as an inverse agonist of RORc; whereas, the same ligand functioned as an agonist of FXR, LXR, and PXR. The structural data was also used to design inhibitors with improved RORc biochemical and cellular activities. The improved inhibitors possessed enhanced selectivity profiles (rationalized using the X-ray crystallographic data) against other nuclear receptors.
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Fauber.Benjamin@gene.com.
Benjamin P
BP
Fauber
Gladys
G
de Leon Boenig
Brenda
B
Burton
Céline
C
Eidenschenk
Christine
C
Everett
Alberto
A
Gobbi
Sarah G
SG
Hymowitz
Adam R
AR
Johnson
Marya
M
Liimatta
Peter
P
Lockey
Maxine
M
Norman
Wenjun
W
Ouyang
Olivier
O
René
Harvey
H
Wong
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D054314:Drug Inverse Agonism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000378:metabolism; D020005:Propanols / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D006845:Hydrocarbons, Fluorinated; D007371:Interferon-gamma; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020005:Propanols; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C001337:hexafluoroisopropanol
Autoimmune; IL-17; Inflammation; RORc; RORγ; T0901317; X-ray structure