title: Synthesis and biological evaluation of partially fluorinated antiprogestins and mesoprogestins.
abstract: A series of antiprogestins have been synthesized by partially fluorinating the steroid molecule in positions relevant for receptor binding. By introducing fluorine at the exo-methylene of the 17 spirofuran ring, we obtained partial agonists (mesoprogestins) with significant applications for antiproliferative and antiovulatory treatment strategies in gynecological therapy such as uterine fibroids, endometriosis and heavy menstrual bleeding. Compared to the standard drug RU486, our synthesized compounds exhibited considerable dissociation between antiprogestational and antiglucocorticoid PR receptors. Furthermore, our studies have shown that pure antiprogestins can be generated by partially fluorinating the 17 propenyl and propynl group or by substituting the 4' acetyl phenyl group in the 11 position using trifluromethyl group.
authors.affiliation: Evestra, Inc., San Antonio, TX, USA. knickisch@evestra.com
authors.forename: Klaus
authors.initials: K
authors.lastname: Nickisch
authors.forename: Walter
authors.initials: W
authors.lastname: Elger
authors.forename: James
authors.initials: J
authors.lastname: Cessac
authors.forename: Narkunan
authors.initials: N
authors.lastname: Kesavaram
authors.forename: Baishakhi
authors.initials: B
authors.lastname: Das
authors.forename: Robert
authors.initials: R
authors.lastname: Garfield
authors.forename: Shao-Qing
authors.initials: SQ
authors.lastname: Shi
authors.forename: Olga
authors.initials: O
authors.lastname: Amelkina
authors.forename: Reinhard
authors.initials: R
authors.lastname: Meister
mesh_terms: D000818:Animals; D005260:Female; D006168:Guinea Pigs; D057809:HEK293 Cells; D054879:Halogenation / Q000187:drug effects*; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015735:Mifepristone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011372:Progestins / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D014621:Vagina / Q000166:cytology / Q000187:drug effects
chemical_list: D006727:Hormone Antagonists; D011372:Progestins; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D015735:Mifepristone