Synthesis and pharmacological evaluation of new progesterone esters as 5α-reductase inhibitors

Abstract

In this study we report the synthesis and pharmacological evaluation of four new progesterone derivatives; 17α-hydroxy-16β-methylpregna-4,6- diene-3,20-dione 12, 17α-cyclopropylcarbonyloxy-16β-methylpregna-4,6- diene-3,20-dione 13, 17α-cyclobutylcarbonyloxy-16β-methylpregna-4,6- diene-3,20-dione 14, 17α-acetoxy-16β-methylpregna-4,6-diene-3,20- dione 15 and the pregnatriene compound 17α-cyclobutylcarbonyloxy-16β- methylpregna-1,4,6-triene-3,20-dione 16. The pharmacological effect of these compounds was determined in vivo as well as in vitro. The evaluation in vivo was carried out on gonadectomized male hamsters that were injected subcutaneously daily with testosterone (T) and/or finasteride, or with the novel compounds. At the end of the treatments the animals were sacrificed and the prostates were weighed. It was observed that when testosterone (T) and finasteride or compounds 12-16 were injected together, the weight of the prostate decreased significantly as compared to that of the testosterone-treated animals. The 5α-reductase inhibitory activity was evaluated in vitro using human prostate homogenates. These experiments showed the following IC50 values: compound 12 (alcohol at C-17) 1.2×10-6M, 13 (cyclopropyl substituent at C-17) 7.9×10-10M, 14 (cyclobutyl substituent) 3.2×10-8M, 15 (acetoxy substituent) 6.3×10-11M and 16 (cyclobutyl substituent) 3.9×10 -6M. It is evident from these data that when the size of the substituent at C-17 is decreased, the 5α-reductase inhibitory activity increases. Apparently, in this biological model, the 5α-reductase inhibitory activity depends upon the steric effect of the substituent at C-17. However, the free alcohol 12 showed much lower 5α-reductase inhibitory activity. © 2005 Pharmaceutical Society of Japan.