title: Synthesis and identification of novel oxa-steroids as progesterone receptor antagonists.
abstract: A novel series of oxa-steroids 6 derived from (8S, 13S, 14R)-7-oxa-estra-4,9-diene-3,17-dione 1 have been synthesized and identified as potent and selective progesterone receptor antagonists. These novel oxa-steroids showed similar potency to mifepristone. Preliminary SAR study resulted in the most potent 17-phenylethynyl oxa-steroid 6i wih an IC(50) of 1.4nM. In contrast to the equipotent mifepristone toward the progesterone receptor (PR) and glucocorticoid receptor (GR), compound 6i had over 200-fold selectivity for PR over GR.
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: George
authors.initials: G
authors.lastname: Allan
authors.forename: Jihua
authors.initials: J
authors.lastname: Guan
authors.forename: Nareshkumar
authors.initials: N
authors.lastname: Jain
authors.forename: Olivia
authors.initials: O
authors.lastname: Linton
authors.forename: Pamela
authors.initials: P
authors.lastname: Tannenbaum
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: Xin
authors.initials: X
authors.lastname: Chen
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: D000469:Alkaline Phosphatase / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000201:enzymology; D045744:Cell Line, Tumor; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D006727:Hormone Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000138:chemical synthesis / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013256:Steroids / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D013256:Steroids; D015735:Mifepristone; D000469:Alkaline Phosphatase