title: Synthesis and pharmacological evaluation of new progesterone esters as 5alpha-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.
authors.affiliation: Department of Pharmacy, Faculty of Chemistry, National University of Mexico City, Mexico DF, Mexico. elenitarl@yahoo.com.mx
authors.forename: Elena
authors.initials: E
authors.lastname: Ramírez
authors.forename: Marisa
authors.initials: M
authors.lastname: Cabeza
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
authors.forename: Ivonne
authors.initials: I
authors.lastname: Heuze
authors.forename: Víctor
authors.initials: V
authors.lastname: Pérez
authors.forename: David
authors.initials: D
authors.lastname: Valdez
authors.forename: Martha
authors.initials: M
authors.lastname: Ochoa
authors.forename: Nayeli
authors.initials: N
authors.lastname: Teran
authors.forename: Geidy
authors.initials: G
authors.lastname: Jimenez
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramírez
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008647:Mesocricetus; D009919:Orchiectomy; D011374:Progesterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D011467:Prostate / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013256:Steroids / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D004952:Esters; D013256:Steroids; D011374:Progesterone; D018120:Finasteride