Androgenic activity unsaturation

Comparison of 17a-methyltestosterone (S-2), 17a-methyl-5a-dihydro-testosterone (D-2), and 17o -methyl-d -testosterone (S-107) revealed that the presence of the double bond in the 4,5-position enhanced the anabolic activity and did not alter the androgenic activity, according to Beyler et al. [124]. Additional unsaturation lowered both anabolic and androgenic activities, but decreased the anabolic activity to a lesser degree. 

Comparison of 17a-methyl-17)8-hydroxy-5a -androstano[3,2-r] pyrazole (D-l 1), 17a-methyl-17)8-hydroxyandrost-4-eno[3,2-c]pyrazole (A-157), and 17a-methyl-17/3-hydroxyandrost-4,6-dieno[3,2-c]pyrazole (A-168) showed that as the degree of unsaturation is increased there is a corresponding decrease in the anabolic and androgenic activities, with the last compound (A-168) having complete loss of these activities. It was suggested [124] that the anabolic and androgenic properties of this compound were lost due to the flattening imposed by the steroidal diene system. It was also found that introduction of an additional double bond between carbons 6 and 7 in 4-chlorotestosterone acetate (S-I48) results in the complete loss of activity (compare with S-146). 

The 3-substituted A -derivatives have already been considered under 3-substitution. Introduction of 5,6-unsaturation into the saturated 5a-androstan-17)3-ol causes decreases in both potencies the assistance provided by the electron cloud of this substitution at this position must not be important. 17j8-Hydroxyandrost-5-ene (A-49) and 17a-methyl-17j8-hydroxyandrost-5-ene (A-59) both show decreased androgenic and anabolic potencies and an unfavorable ratio compared to the parent saturated compound. Additional unsaturation between carbons 3 and 4 will further decrease the activities. 17/3-Hydroxyandrost-3,5-diene (A-150) and 17a-methyl-17j8-hydroxyandrost-3,5-diene (A-48) show decreased activities compared to the A -analogs, A-49 and A-59, or to 17/3-hydroxyandrost-3-ene (A-3). 

The facts that inversion of configuration at C-9 is possible without abolishing the activity and that removal of the hydrogen (introduction of unsaturation between carbons 9 and 10) sometimes decreases (N-96) the androgenic and anabolic potencies and in many cases increases both potencies, point to the lack of importance of attachment to the receptor at carbon-9. Substitution of the 9-hydrogen by bulkier substituents usually decreases the activity but in the case of fluorine it increases it (S-19 and S-25). Removal of the 9-hydrogen and the simultaneous introduction of unsaturation between carbons 11 and 12 greatly enhances the activities. These facts also point to the uninvolvement of C-9 in the attachment to the receptor site. 

Extension of unsaturation also increases the androgenic and anabolic activities in some cases. The heteroannular dienone, l3/3,17a-diethyl-17/3-hydroxygona-4,9(10j-dien-3-one (N-98) and several heteroannular trienones, 7a,17a-dimethyl-17/3-hydroxyestra-4,9(10),l l-trien-3-one (N-102), 17j8-acetoxyestra-4,9(10),l l-trien-3-one (N-103), 17/3-methoxy-methyloxyestra-4,9,1 l-trien-3-one (N-104), 17/3-hydroxyestra-4,9,l 1-trien-3-one-17- -decanoate (N-105), and 17/3-hydroxyestra-4,9,l 1-trien-3-one 17-carbobenzoxyate (N-106) all exhibit very large increases in both androgenic and anabolic activities. The ratio is not favorable. 

Further unsaturation of the B or C ring of 19-androstane derivatives usually enhances progestin activity. Introduction of a halogen or methyl substituent in the 6a or 7a positions generally increases hormonal activity. Acetylation of the 17p-OH of norethindrone increases the duration of action of the drug. Removal of the 3-keto function of norethindrone allows retention of potent progestin activity and no androgenic effects. 

The naturally occurring androgenic hormones possess the 19-carbon steroid nucleus with an oxygen function at Ci7 instead of a side chain. Testosterone (L) is biologically the most active androgen and is the chief male hormone of the testis. It has an a,jS-unsaturated ketone in ring A and... 

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