Recent advances in the chemistry and pharmacological activity of new steroidal antiandrogens and 5 alpha-reductase inhibitors.

Abstract

The object of this paper is to summarize for the past two years the most recent development in the field of prostate cancer and 5 alpha-reductase inhibitors. In addition we are also including some results on the synthesis and pharmacological evaluation of new steroidal compounds developed in our laboratory. Most of the new steroidal derivatives are based on the progesterone skeleton and showed a high inhibitory activity for the enzyme 5 alpha-reductase. Presently, similar compounds are used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, benign prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. 1) a 5 alpha-reduced metabolite of testosterone 1 has been implicated as a causative factor for the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of the enzyme steroid 5 alpha-reductase. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 7 (Fig. 3) a 5 alpha-reductase inhibitor has greatly alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory, we recently synthesized several new 16 beta-methylpregnadiene-3,20-diones: 40, 41 (Fig. 8), 16 beta-phenylpregnadiene-3,17a-dione derivatives 46 and 47 (Fig. 9) and 49 (C-4 bromoderivative) (Fig. 11), 52-56 (Fig. 13). The analogue pregnatriene derivatives were also prepared: 44, 45 (Fig. 9) 50, 51 (Fig. 11) and 57-60 (Fig. 13) These compounds were evaluated as 5 alpha-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles of homogenates of gonadectomized male hamsters. All trienones 44, 45, 50, 51 and 57-60 in all biological models showed consistently a higher 5 alpha-reductase inhibitory activity than the corresponding dienones: 40, 41, 46, 47, 49 and 52-56. We believe that with these compounds the 5 alpha-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme thus showing a higher inhibitory activity.

• Authors: Eugene Bratoeff, Marisa Cabeza, Elena Ramirez, Yvonne Heuze, Eugenio Flores
• Journal: Current medicinal chemistry (Curr Med Chem) Vol. 12 Issue 8 Pg. 927-43 ( 2005) ISSN: 0929-8673 [Print] United Arab Emirates
• PMID: 15853706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Androgen Antagonists
• Enzyme Inhibitors
• Steroids
• Cholestenone 5 alpha-Reductase

Topics

• Androgen Antagonists (chemical synthesis, chemistry, pharmacology)
• Animals
• Cholestenone 5 alpha-Reductase (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Male
• Phytotherapy
• Prostatic Neoplasms (drug therapy)
• Steroids (chemical synthesis, chemistry, pharmacology)