Novel synthesis of the hexahydroimidazo[1,5b]isoquinoline scaffold: application to the synthesis of glucocorticoid receptor modulators.
Article Details
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Xiao HY, Wu DR, Malley MF, Gougoutas JZ, Habte SF, Cunningham MD, Somerville JE, Dodd JH, Barrish JC, Nadler SG, Dhar TG
Novel synthesis of the hexahydroimidazo[1,5b]isoquinoline scaffold: application to the synthesis of glucocorticoid receptor modulators.
J Med Chem. 2010 Feb 11;53(3):1270-80. doi: 10.1021/jm901551w.
- PubMed ID
- 20047280 [ View in PubMed]
- Abstract
The first stereoselective synthesis of the hexahydroimidazo[1,5b]isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (GR) in terms of binding affinity, although the partial agonist activity in the transrepressive assays depends on the substitution pattern on the B-ring. More importantly, most compounds in the HHII series bearing a tertiary alcohol moiety on the B-ring are either inactive or significantly less active in inducing GR-mediated transactivation, thus displaying a "dissociated" pharmacology in vitro.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Dexamethasone Glucocorticoid receptor EC 50 (nM) 2.5 N/A N/A Details Dexamethasone Glucocorticoid receptor EC 50 (nM) 1.1 N/A N/A Details Dexamethasone Glucocorticoid receptor Ki (nM) 1.2 N/A N/A Details Dexamethasone Glucocorticoid receptor EC 50 (nM) 4.5 N/A N/A Details