title: In vitro and in vivo characterization of novel nonsteroidal progesterone receptor antagonists derived from the fungal metabolite PF1092C.
abstract: We studied the pharmacological effects of novel nonsteroidal progesterone receptor antagonists CP8661 and CP8754, which were synthesized from the fungal metabolite PF1092C. CP8661 possess a tetrahydrobenzindolone skeleton and CP8754 possess a tetrahydronaphthofuranone skeleton. In binding assays for steroid receptors, CP8661 and CP8754 inhibited [(3)H]-progesterone binding to human progesterone receptors (hPR), though they are less potent than RU486. CP8661 also showed moderate affinity to rat androgen receptors (rAR), although CP8754 did not. Neither compound showed affinity to human glucocorticoid receptors (hGR) or human estrogen receptors (hER). In exogeneous and endogeneous PR-dependent enzyme expression assays using human mammary carcinoma T47D, CP8661 and CP8754 showed pure antagonistic activity. In a rabbit endometrial transformation test, CP8661 and CP8754 showed anti-progestational activity by s.c. administration in a dose-dependent manner; meanwhile, these compounds showed no progestational activity at the same dose. These results suggested that CP8661 and CP8754 are in vivo effective pure progesterone receptor antagonists and presented the possibility of synthesizing pure progesterone receptor antagonists from both tetrahydronaphthofuranone and tetrahydrobenzindolone skeletons.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho Kohoku-ku, Yokohama, 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: Naomi Takei
authors.initials: NT
authors.lastname: Masuda
authors.forename: Rie
authors.initials: R
authors.lastname: Shinei
authors.forename: Ken ichi
authors.initials: Ki
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: D000818:Animals; D001681:Biological Assay; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006727:Hormone Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009284:Naphthols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C470519:CP8661; C470520:CP8754; D004967:Estrogens; D006727:Hormone Antagonists; D009284:Naphthols; C106750:PF 1092C; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012717:Sesquiterpenes; D011374:Progesterone