title: CP8668, a novel orally active nonsteroidal progesterone receptor modulator with tetrahydrobenzindolone skeleton.
abstract: We investigated progestational activity of a new nonsteroidal compound, CP8668, ((4aR,5R,6R,7R)-7-methoxy-6-(N-propylaminocarbonyl)oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one). CP8668 showed selective affinity for human progesterone receptor equal in strength to other steroidal progestins. CP8668 showed no significant affinity for human glucocorticoid receptor or human estrogen receptor and very weak affinity for rat androgen receptor. In endogenous and exogenous progesterone-dependent enzyme expression assays using human mammary carcinoma T47D, CP8668 showed mixed agonist-antagonist activity. However, in a rabbit endometrial transformation test, CP8668 showed good progestational activity following s.c. and p.o. administration. These results suggest that CP8668 is a selective and orally active progesterone receptor modulator, which shows mixed agonist-antagonist activity in in vitro transcription tests and agonist activity in endometrial transformation assays in rabbits, and that it is potentially a promising lead compound for a new type of orally active progesterone receptor modulator.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. yuji_tabata@meiji.co.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tabata
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Iizuka
authors.forename: Rie
authors.initials: R
authors.lastname: Shinei
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kurihara
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Okonogi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hoshiko
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kurata
mesh_terms: D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D011817:Rabbits; D011869:Radioligand Assay; D011980:Receptors, Progesterone / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C476228:(4aR,5R,6R,7R)-7-methoxy-6-(N-propylaminocarbonyl)oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz(f)indol-2(4H)-one; D007211:Indoles; D011980:Receptors, Progesterone; D000469:Alkaline Phosphatase