Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series.
The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.
Barker
Mike
M
RI CEDD, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
Clackers
Margaret
M
Copley
Royston
R
Demaine
Derek A
DA
Humphreys
Davina
D
Inglis
Graham G A
GG
Johnston
Michael J
MJ
Jones
Haydn T
HT
Haase
Michael V
MV
House
David
D
Loiseau
Richard
R
Nisbet
Lesley
L
Pacquet
Francois
F
Skone
Philip A
PA
Shanahan
Stephen E
SE
Tape
Dan
D
Vinader
Victoria M
VM
Washington
Melanie
M
Uings
Iain
I
Upton
Richard
R
McLay
Iain M
IM
Macdonald
Simon J F
SJ
D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D011869:Radioligand Assay; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; 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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D048588:Benzoxazines; D011965:Receptors, Glucocorticoid; D013764:Tetrahydronaphthalenes; D003907:Dexamethasone