Synthesis and Pharmacological Evaluation of New Progesterone Esters as 5.ALPHA.-Reductase Inhibitors

Abstract

In this study we report the synthesis and pharmacological evaluation of four new progesterone derivatives; 17alpha-hydroxy-16beta-methylpregna-4,6-diene-3,20-dione 12, 17alpha-cyclopropylcarbonyloxy-16beta-methylpregna-4,6-diene-3,20-dione 13, 17alpha-cyclobutylcarbonyloxy-16beta-methylpregna-4,6-diene-3,20-dione 14, 17alpha-acetoxy-16beta-methylpregna-4,6-diene-3,20-dione 15 and the pregnatriene compound 17alpha-cyclobutylcarbonyloxy-16beta-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 5alpha-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 x 10(-6) M, 13 (cyclopropyl substituent at C-17) 7.9 x 10(-10) M, 14 (cyclobutyl substituent) 3.2 x 10(-8) M, 15 (acetoxy substituent) 6.3 x 10(-11) M and 16 (cyclobutyl substituent) 3.9 x 10(-6) M. It is evident from these data that when the size of the substituent at C-17 is decreased, the 5alpha-reductase inhibitory activity increases. Apparently, in this biological model, the 5alpha-reductase inhibitory activity depends upon the steric effect of the substituent at C-17. However, the free alcohol 12 showed much lower 5alpha-reductase inhibitory activity.

Steroidal 5α-Reductase Inhibitors: A Comparative 3D-QSAR Study Review

“…Cabeza et al reported the synthesis and human steroidal 5α-reductase-II inhibitory activities of several series of pregnane derivatives having diversity in structure and potency profile (Figure ). A 3D-QSAR study was reported on a data set of 30 molecules of pregnane series in our laboratory. − …”

“…A wide variety of data sets bearing 4-azasteroids (Finasteride analogues), , 3-carboxysteroids (Epristeride analogues), pregnane scaffold, − and 6-azasteroids − as potential inhibitors of steroidal 5α-reductase were employed for the present comparative 3D-QSAR studies. Data sets where the inhibitory activities of these compounds were measured by a single protocol and derived from the same laboratory were selected in each study.…”