Novel synthesis of the hexahydroimidazo[1,5b]isoquinoline scaffold: application to the synthesis of glucocorticoid receptor modulators.

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
DexamethasoneGlucocorticoid receptorEC 50 (nM)2.5N/AN/ADetails
DexamethasoneGlucocorticoid receptorEC 50 (nM)1.1N/AN/ADetails
DexamethasoneGlucocorticoid receptorKi (nM)1.2N/AN/ADetails
DexamethasoneGlucocorticoid receptorEC 50 (nM)4.5N/AN/ADetails