title: Parallel synthesis and SAR study of novel oxa-steroids as potent and selective progesterone receptor antagonists.
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.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19341, USA. fkang@prdus.jnj.com
authors.forename: Fu-An
authors.initials: FA
authors.lastname: Kang
authors.forename: Jihua
authors.initials: J
authors.lastname: Guan
authors.forename: Nareshkumar
authors.initials: N
authors.lastname: Jain
authors.forename: George
authors.initials: G
authors.lastname: Allan
authors.forename: Olivia
authors.initials: O
authors.lastname: Linton
authors.forename: Pamela
authors.initials: P
authors.lastname: Tannenbaum
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Peifang
authors.initials: P
authors.lastname: Zhu
authors.forename: Joseph
authors.initials: J
authors.lastname: Gunnet
authors.forename: Keith
authors.initials: K
authors.lastname: Demarest
authors.forename: Scott
authors.initials: S
authors.lastname: Lundeen
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003176:Complement C3 / Q000378:metabolism; D015195:Drug Design; D005260:Female; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D008956:Models, Chemical; D011485:Protein Binding; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D013256:Steroids / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D003176:Complement C3; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D013256:Steroids; D015735:Mifepristone