title: Effects of the novel orally active antiestrogen TZE-5323 on experimental endometriosis.
abstract: Danazol and gonadotropin-releasing hormone agonists which are used as therapeutic drugs for endometriosis, develop adverse reactions in association with their long-term use. The efficacy of anti-estrogens for endometriosis, an estrogen-dependent disorder, has not been demonstrated. A novel, orally active anti-estrogen, TZE-5323 ((2-cyclohexy-6-hydroxybenzo[b]thien-3-yl)[4-[2-(1- piperidinyl)ethoxy]phenyl] methanone hydrochloride, CAS 150797-71-0; free salt formula) was developed. TZE-5323 showed strong affinity for human estrogen receptor alpha (hER alpha) and beta (hER beta), and dose-dependently inhibited estradiol-stimulated transcriptional activation via hER alpha and hER beta. Furthermore, TZE-5323 dose-dependently reduced estrogen-increased uterine weight in ovariectomized rats. Tamoxifen showed agonistic activity on hER alpha, while TZE-5323 did not show such activity. In the experimental endometriosis model in rats in which endometrial tissue is autotransplanted into the renal subcapsular space, TZE-5323 dose-dependently reduced the volume of the endometrial implant as did danazol and leuprorelin acetate. Furthermore, the long-term administration of TZE-5323 neither showed a decrease in bone mineral density nor did it affect serum estradiol concentrations in intact rats. Therefore, TZE-5323 suggested its potential as a novel therapeutic drug for endometriosis which is effective also in long-term use.
authors.affiliation: Pharmacology Department, Teikoku Hormone Mfg. Co., Ltd., Kawasaki, Kanagawa, Japan. saito-t1@kw.teikoku-hormone.co.jp
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Saito
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshizawa
authors.forename: Yukinao
authors.initials: Y
authors.lastname: Yamauchi
authors.forename: Setsuo
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Tomohito
authors.initials: T
authors.lastname: Fujii
authors.forename: Mamoru
authors.initials: M
authors.lastname: Mieda
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sone
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Koizumi
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004715:Endometriosis / Q000188:drug therapy*; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D004958:Estradiol / Q000097:blood; D004965:Estrogen Antagonists / Q000378:metabolism / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D008024:Ligands; D009929:Organ Size / Q000187:drug effects; D010880:Piperidines / Q000378:metabolism / Q000627:therapeutic use*; D010957:Plasmids / Q000235:genetics; D014176:Protein Biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects; D014599:Uterus / Q000187:drug effects
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D010880:Piperidines; D011960:Receptors, Estrogen; C477839:(2-cyclohexy-6-hydroxybenzo(b)thien-3-yl)(4-(2-(1- piperidinyl)ethoxy)phenyl) methanone hydrochloride; D004958:Estradiol; D002784:Cholesterol; D015500:Chloramphenicol O-Acetyltransferase