In the search for new antiandrogens, a number of des-A-steroids were prepared by condensation of Grignard reagents with lactone 3. From the resulting key intermediates 5, various structural modifications were performed such as the introduction of an additional unsaturation to afford dienones 8 and aromatic derivatives 10 or the introduction of an alkyl substituent mostly in position 10 (11-13) but also in some cases in position 16 (22). In addition, 13-ethyl analogues were also prepared from lactone 4. The relative binding affinities (RBAs) for the androgen receptor of these compounds were determined under various conditions. Some compounds exhibit a capacity to interact with the receptor comparable to that of testosterone. One of the most potent compounds is 17beta-hydroxy-des-A-androsta-9,11-dien-5-one (8b), RBA value 73% of that of testosterone. More interestingly, several compounds were found to have an antiandrogenic profile in vitro and in vivo. One of the most effective compounds is 10-ethyl-17beta-hydroxy-des-A-estra-9-en-5-one (5c), which exhibits a strong local antiandrogenic activity in hamsters, without any significant systemic antiandrogenic effects. The corresponding 17beta-acetyl derivative (RU 38882) has been selected for extended pharmacological studies.
Journal Article The quail uropygial gland for assays of systemic antiandrogen side‐effects of topical drugs Get access J.Y. DANIEL, J.Y. DANIEL Laboratoire de Biologie Cellulaire, Faculté de Médecine, Brest Search for other works by this author on: Oxford Academic Google Scholar J.H. ABALAIN, J.H. ABALAIN Laboratoire de Biochimie, UA 598 du CNRS, Faculté de Médecine, Brest Dr J.H.Abalain. Search for other works by this author on: Oxford Academic Google Scholar Y. AMET, Y. AMET Laboratoire de Biochimie, UA 598 du CNRS, Faculté de Médecine, Brest Search for other works by this author on: Oxford Academic Google Scholar S. DI STEFANO, S. DI STEFANO Laboratoire de Biochimie, UA 598 du CNRS, Faculté de Médecine, Brest Search for other works by this author on: Oxford Academic Google Scholar F. BERTHOU, F. BERTHOU Laboratoire de Biochimie, UA 598 du CNRS, Faculté de Médecine, Brest Search for other works by this author on: Oxford Academic Google Scholar K. TEA, K. TEA Laboratoire de Biochimie, UA 598 du CNRS, Faculté de Médecine, Brest Search for other works by this author on: Oxford Academic Google Scholar H.H. FLOCH, H.H. FLOCH Laboratoire de Biochimie, UA 598 du CNRS, Faculté de Médecine, Brest Search for other works by this author on: Oxford Academic Google Scholar M.M. BOUTON, M.M. BOUTON Centre de Recherches Roussel‐Uclaf, Romainville, France Search for other works by this author on: Oxford Academic Google Scholar J. SECCHI J. SECCHI Centre de Recherches Roussel‐Uclaf, Romainville, France Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 115, Issue s31, 1 August 1986, Pages 33–35, https://doi.org/10.1111/j.1365-2133.1986.tb02104.x Published: 01 August 1986
Transferrin mRNA content and gene transcription rate were measured in the liver of rats submitted to iron overload or depletion, castration, treatment with sexual steroid hormones, glucagon and cyclic AMP. The influence of puberty in males and females and of pregnancy was also analysed. Glucagon and cyclic AMP reduced mRNA level by about 50% at the 12th hour of treatment and transferrin gene transcription by as muchas 95% at the 30th minute of drug infusion, with a secondary increase of the transcription rate for a protracted treatment. None of the other hormones tested had any detectable effect on transferrin gene expression, the same being true for iron overload or depletion.
The study of the kinetics of the interaction between two ethynyl estradiol derivatives (llβ-methoxy-17-ethynyl-l,3,5(10)-estratriene-3,17β-diol and llα-methoxy-17-ethynyl-l,3,5(10)-estratriene-3,17β-diol), differing in the configuration of the 11-methoxy substituent, and the cytoplasmic estrogen receptor in mouse uterus and the study of their ability to induce short and long term estrogen responses (uterine weight increase, estrogen receptor replenishment, and progestin receptor induction) in the mouse have led to the following conclusions. Potent agonists are compounds which form slowly dissociating cytoplasmic receptor complexes. Low doses of weak agonists are able to induce short term responses to the same extent as potent agonists but are unable to maintain these responses; higher doses or frequent administration are required to maintain an effect. The degree of agonist activity is related to the nuclear estrogen receptor concentration, which is in turn related to the ability of the ligand to form a stable cytoplasmic receptor complex. Low doses of weak agonists can effectively compete with endogenous hormone for cytoplasmic receptor sites and thus prevent the endogenous hormone from inducing its full biological response. Since they are themselves unable to induce a full response, this competition results in antihormonal activity.
