Biological activity of novel progesterone derivatives having a bulky ester side chains at C-3

Antiandrogens are widely used agents for the treatment of androgen dependent diseases as inhibitors of androgen receptors (AR) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of the structure of the ligand in relation with the nuclear co-repressors. In the present study, we investigated the relationship between log P (the partition coefficient) of four pregnane derivatives 9a-9d and their biological activity. For this purpose, we determined the relative binding affinity (RBA) of steroids 9a-9d to androgen receptor (AR) obtained from rat prostate cytosol, using labeled mibolerone (MIB) as ligand. The IC(50) value of each compound was calculated according to the plots of concentration versus percentage of binding. The in vivo effect of 9a-9d was determined on the weight of the prostate and seminal vesicles from castrated hamsters treated with dihydrotestosterone. The four compounds bind to the androgen receptor with different relative binding affinity (RBA). Compound 9d having a log P of 4.17 showed the highest RBA > 100% as compared to compound 9a having a log P of 2.92 which exhibited a RBA of only 2.85%. These data show a very good correlation between the lipophilicity of these compounds represented by log P and the percentage of RBA. The in vivo experiments showed that all new compound 9a-9d reduced the weight of the prostate gland as well as the seminal vesicles. Steroids 9c and 9d having a log P of 3.75 and 4.17, respectively, showed the highest antiandrogenic effect. (C) 2008 Elsevier Inc. All rights reserved.