Pharmacological Profile of 9,11-Dehydrocortexolone 17α-Butyrate (CB-03-04), a New Androgen Antagonist with Antigonadotropic Activity

Abstract

A series of new cortexolone-related derivatives has been synthesized and investigated for potential anti-androgenic activity. Among the steroids evaluated, 9,11-dehydrocortexolone 17alpha-butyrate (CB-03-04) was the most promising one. The compound displayed a strong local antiandrogenic activity in hamster's flank organ test, and it was also found to be effective in the rat after subcutaneous injection. When compared to other well known androgen antagonists, the rank order of topical anti-androgenic activity in that test was: cyproterone acetate (CAS 427-51-0) > or = CB-03-04 > finasteride (CAS 98319-26-7) > flutamide (CAS 13311-84-7). In addition, the steroid had selective antigonadotropic activity, when injected into parabiotic rats, and was about as active as progesterone. The activity of CB-03-04 was ascribed mainly to its ability to compete with the stimulating effects of testosterone and dihydrotestosterone and, concurrently, to inhibit the gonadotropins hypersecretion. This bimodal mechanism of action could be predictive for the clinical usefulness of the steroid in the treatment of prostate cancer and benign prostate hypertrophy.

A full conformational characterization of antiandrogen cortexolone-17α-propionate and related compounds through theoretical calculations and nuclear magnetic resonance spectroscopy

“…Differently from the 17a-monoesters of cortexolone, 9,11dehydrocortexolone-17a-butyrate (9) was found to show systemic activity in the rat aer subcutaneous injection. 12 Compound 9 was also discovered to be a potent inhibitor of gonadotropin hypersecretion, thus mimicking the activity prole of cyproterone acetate (7), which blocks the androgen-receptor interaction and simultaneously reduces serum testosterone through its antigonadotropic action. 13,14 The presence of a double bond at position 9,11 of the cortexolone, modifying the spatial conformation of the steroids rings, could be responsible for the systemic and increased topical activity of 9.…”

“…13,14 The presence of a double bond at position 9,11 of the cortexolone, modifying the spatial conformation of the steroids rings, could be responsible for the systemic and increased topical activity of 9. 12…”