Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity.
The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.
Biggadike
Keith
K
ri CEDD, GlaxoSmithKline Medicines Research Centre, Stevenage, UK.
Boudjelal
Mohamed
M
Clackers
Margaret
M
Coe
Diane M
DM
Demaine
Derek A
DA
Hardy
George W
GW
Humphreys
Davina
D
Inglis
Graham G A
GG
Johnston
Michael J
MJ
Jones
Haydn T
HT
House
David
D
Loiseau
Richard
R
Needham
Deborah
D
Skone
Philip A
PA
Uings
Iain
I
Veitch
Gemma
G
Weingarten
Gordon G
GG
McLay
Iain M
IM
Macdonald
Simon J F
SJ
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D054333:Drug Partial Agonism; D006801:Humans; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors; 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; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D013764:Tetrahydronaphthalenes