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: Tomoyuki Saito, Masayuki Yoshizawa, Yukinao Yamauchi, Setsuo Kinoshita, Tomohito Fujii, Mamoru Mieda, Hideyuki Sone, Yoshiko Yamamoto, Naoyuki Koizumi
• Journal: Arzneimittel-Forschung (Arzneimittelforschung) Vol. 53 Issue 7 Pg. 507-14 ( 2003) ISSN: 0004-4172 [Print] Germany
• PMID: 12918217 (Publication Type: Journal Article)

Chemical References

• Estrogen Antagonists
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Ligands
• Piperidines
• Receptors, Estrogen
• (2-cyclohexy-6-hydroxybenzo(b)thien-3-yl)(4-(2-(1- piperidinyl)ethoxy)phenyl) methanone hydrochloride
• Estradiol
• Cholesterol
• Chloramphenicol O-Acetyltransferase

Topics

• Animals
• Bone Density (drug effects)
• Chloramphenicol O-Acetyltransferase (metabolism)
• Cholesterol (blood)
• Endometriosis (drug therapy)
• Endometrium (drug effects, pathology)
• Estradiol (blood)
• Estrogen Antagonists (metabolism, therapeutic use)
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Female
• Ligands
• Organ Size (drug effects)
• Piperidines (metabolism, therapeutic use)
• Plasmids (genetics)
• Protein Biosynthesis
• Rats
• Rats, Wistar
• Receptors, Estrogen (genetics, metabolism)
• Transcription, Genetic
• Transcriptional Activation (drug effects)
• Uterus (drug effects)