Design and synthesis of new nonsteroidal glucocorticoid modulators through application of an "agreement docking" method.
Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.
ri CEDD, GlaxoSmithKline Medicines Research Centre, Stevenage, UK.
Mike
M
Barker
Margaret
M
Clackers
Derek A
DA
Demaine
Davina
D
Humphreys
Michael J
MJ
Johnston
Haydn T
HT
Jones
Francois
F
Pacquet
John M
JM
Pritchard
Mark
M
Salter
Stephen E
SE
Shanahan
Philip A
PA
Skone
Victoria M
VM
Vinader
Iain
I
Uings
Iain M
IM
McLay
Simon J F
SJ
Macdonald
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D008024:Ligands; D011965:Receptors, Glucocorticoid; D013764:Tetrahydronaphthalenes