Jupiter1
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We have some promising results for the following steroid: AKA 2.2.1.2. 3ß-Acetoxy-5-hydroxypregn-16-ene-6,20-dione 6
Steroids Volume 70, Issue 3 , March 2005, Pages 217-224 New 5a-reductase inhibitors: In vitro and in vivo effects
VÃctor Pérez-Ornelasa, Marisa Cabezab, , , Eugene Bratoeffa, Ivonne Heuzeb, Mauricio Sánchezb, Elena RamÃreza and Elia Naranjo-RodrÃgueza
Abstract The enzyme 5a-reductase is responsible for the conversion of testosterone (T) to its more potent androgen dihydrotestosterone (DHT). This steroid had been implicated in androgen-dependent diseases such as: benign prostatic hyperplasia, prostate cancer, acne and androgenic alopecia. The inhibition of 5a-reductase enzyme offers a potentially useful treatment for these diseases.
In this study, we report the synthesis and pharmacological evaluation of several new 3-substituted pregna-4, 16-diene-6, 20-dione derivatives. These compounds were prepared from the commercially available 16-dehydropregnenolone acetate. The biological activity of the new steroidal derivatives was determined in vivo as well as in vitro experiments.
In vivo experiments, the anti-androgenic effect of the steroids was demonstrated by the decrease of the weight of the prostate gland of gonadectomized hamster treated with T plus finasteride or the new steroids. The IC50 value of these steroids was determined by measuring the conversion of radio labeled T to DHT.
The results of this study carried out with 5a-reductase enzyme from hamster and human prostate showed that four of the six steroidal derivatives (5, 7, 9, 10) exhibited much higher 5a-reductase inhibitory activity, as indicated by the IC50 values than the presently used Proscar 3 (finasteride).
The comparison of the weight of the hamster's prostate gland indicated that compound 5 had a comparable weight decrease as finasteride. The overall data of this study showed very clearly those compounds 5, 7, 9, 10 are good inhibitors for the 5a-reductase enzyme.
NOTE: The most extensively studied class of 5a-reductase inhibitors are the 4-azasteroids [6] and [7], which include the drug finasteride
Recently, our group synthesized several new progesterone derivatives that considerably decreased the prostate growth produced by T
DISCUSSION:
The results from this study with hamster and human prostate enzymes showed very clearly that compounds 5, 7, 9 and 10 (Table 1) are much better inhibitors for the enzyme 5a-reductase than the presently used Proscar 3 (finasteride). These results confirm also the similarity of both hamster and human 5a-reductase enzymes. The fact that the optimum pH for hamster's 5a-reductase activity at 2 nM is 7 [13] whereas that for human is 6.5 at the same concentration indicates very clearly that some differences in their activity are present.
Although the active steroidal derivatives 5, 7, 9 and 10 have different functional groups, they all have one moiety in common, the a,ß-unsaturated C-20-carbonyl group.
The result of the toxicological assays carried out with Artemia salina cultures showed very clearly that steroid 5 did not produce any toxicological and lethal effects, and as a consequence of this it could be considered a save compound with high pharmacological potential.
Since compound 5 (AKA 2.2.1.2. 3ß-Acetoxy-5-hydroxypregn-16-ene-6,20-dione 6) is in human prostate enzyme about 100 times more active as 5a-reductase inhibitor than the commercially available Proscar 3 (finasteride) (Table 1) and does not produce any toxicological effects in the near future, this compound will be evaluated on a clinical level. The synthesis of this compound is very simple and much cheaper than that of finasteride 3, and this steroidal derivative could represent a magnificent alternative for the treatment of androgen-dependent diseases.
Steroids Volume 70, Issue 3 , March 2005, Pages 217-224 New 5a-reductase inhibitors: In vitro and in vivo effects
VÃctor Pérez-Ornelasa, Marisa Cabezab, , , Eugene Bratoeffa, Ivonne Heuzeb, Mauricio Sánchezb, Elena RamÃreza and Elia Naranjo-RodrÃgueza
Abstract The enzyme 5a-reductase is responsible for the conversion of testosterone (T) to its more potent androgen dihydrotestosterone (DHT). This steroid had been implicated in androgen-dependent diseases such as: benign prostatic hyperplasia, prostate cancer, acne and androgenic alopecia. The inhibition of 5a-reductase enzyme offers a potentially useful treatment for these diseases.
In this study, we report the synthesis and pharmacological evaluation of several new 3-substituted pregna-4, 16-diene-6, 20-dione derivatives. These compounds were prepared from the commercially available 16-dehydropregnenolone acetate. The biological activity of the new steroidal derivatives was determined in vivo as well as in vitro experiments.
In vivo experiments, the anti-androgenic effect of the steroids was demonstrated by the decrease of the weight of the prostate gland of gonadectomized hamster treated with T plus finasteride or the new steroids. The IC50 value of these steroids was determined by measuring the conversion of radio labeled T to DHT.
The results of this study carried out with 5a-reductase enzyme from hamster and human prostate showed that four of the six steroidal derivatives (5, 7, 9, 10) exhibited much higher 5a-reductase inhibitory activity, as indicated by the IC50 values than the presently used Proscar 3 (finasteride).
The comparison of the weight of the hamster's prostate gland indicated that compound 5 had a comparable weight decrease as finasteride. The overall data of this study showed very clearly those compounds 5, 7, 9, 10 are good inhibitors for the 5a-reductase enzyme.
NOTE: The most extensively studied class of 5a-reductase inhibitors are the 4-azasteroids [6] and [7], which include the drug finasteride
Recently, our group synthesized several new progesterone derivatives that considerably decreased the prostate growth produced by T
DISCUSSION:
The results from this study with hamster and human prostate enzymes showed very clearly that compounds 5, 7, 9 and 10 (Table 1) are much better inhibitors for the enzyme 5a-reductase than the presently used Proscar 3 (finasteride). These results confirm also the similarity of both hamster and human 5a-reductase enzymes. The fact that the optimum pH for hamster's 5a-reductase activity at 2 nM is 7 [13] whereas that for human is 6.5 at the same concentration indicates very clearly that some differences in their activity are present.
Although the active steroidal derivatives 5, 7, 9 and 10 have different functional groups, they all have one moiety in common, the a,ß-unsaturated C-20-carbonyl group.
The result of the toxicological assays carried out with Artemia salina cultures showed very clearly that steroid 5 did not produce any toxicological and lethal effects, and as a consequence of this it could be considered a save compound with high pharmacological potential.
Since compound 5 (AKA 2.2.1.2. 3ß-Acetoxy-5-hydroxypregn-16-ene-6,20-dione 6) is in human prostate enzyme about 100 times more active as 5a-reductase inhibitor than the commercially available Proscar 3 (finasteride) (Table 1) and does not produce any toxicological effects in the near future, this compound will be evaluated on a clinical level. The synthesis of this compound is very simple and much cheaper than that of finasteride 3, and this steroidal derivative could represent a magnificent alternative for the treatment of androgen-dependent diseases.
