Parallel synthesis and SAR study of novel oxa-steroids as potent and selective progesterone receptor antagonists.

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Kang FA, Guan J, Jain N, Allan G, Linton O, Tannenbaum P, Chen X, Xu J, Zhu P, Gunnet J, Demarest K, Lundeen S, Sui Z

Parallel synthesis and SAR study of novel oxa-steroids as potent and selective progesterone receptor antagonists.

Bioorg Med Chem Lett. 2007 May 1;17(9):2531-4. Epub 2007 Feb 8.

PubMed ID
17317167 [ View in PubMed
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Abstract

Efficient parallel synthesis of novel 7-oxa-steroids 4 has been achieved from the key intermediate 3 via a one-pot four-step sequence. oxa-Steroids 4 with various ortho-, meta-, and para-monosubstituents on the phenyl ring, as well as disubstituted phenyl and heterocycles, were evaluated for progesterone receptor (PR) and glucocorticoid receptor (GR) antagonist activities. SAR study demonstrated that the para-fluorinated substituents on the phenyl ring not only increased the potency for PR in a T47D cell functional assay, but also improved the selectivity over GR in an A549 cell functional assay. The para-fluorophenyl oxa-steroid 4l and the para-trifluoromethylphenyl oxa-steroid 4p were found to be remarkably more potent and more selective PR antagonists than mifepristone, with subnanomolar potency and about 140-fold selectivity over GR. Molecular modeling of the oxa-steroid bound to PR provided meaningful insight for the SAR study. oxa-Steroids 4a and 4b were found to be more efficacious than mifepristone in vivo in a rat uterine complement C3 assay via the oral route, although they were less than or equally potent to mifepristone in the T47D assay.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MifepristoneGlucocorticoid receptorIC 50 (nM)1.6N/AN/ADetails
MifepristoneProgesterone receptorIC 50 (nM)1.4N/AN/ADetails