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.
Barker
Mike
M
ri CEDD, GlaxoSmithKline Medicines Research Centre, Stevenage, UK.
Clackers
Margaret
M
Demaine
Derek A
DA
Humphreys
Davina
D
Johnston
Michael J
MJ
Jones
Haydn T
HT
Pacquet
Francois
F
Pritchard
John M
JM
Salter
Mark
M
Shanahan
Stephen E
SE
Skone
Philip A
PA
Vinader
Victoria M
VM
Uings
Iain
I
McLay
Iain M
IM
Macdonald
Simon J F
SJ
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