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]
- 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
Drug Target Property Measurement pH Temperature (°C) Mifepristone Glucocorticoid receptor IC 50 (nM) 1.6 N/A N/A Details Mifepristone Progesterone receptor IC 50 (nM) 1.4 N/A N/A Details