title: Steroid derivatives as pure antagonists of the androgen receptor.
abstract: BACKGROUND
  While the androgens of testicular origin (representing about 50% of total androgens in men over 50 years) can be completely eliminated by surgical or medical castration with GnRH (gonadotropin-releasing hormone) agonists or antagonists, the antiandrogens currently available as blockers of androgen binding to the androgen receptor (AR), namely bicalutamide (BICA), flutamide (FLU) and nilutamide have too weak affinity to completely neutralize the other 50% of androgens made locally from dehydroepiandrosterone (DHEA) in the prostate cancer tissue by the mechanisms of intracrinology.
  
  
  METHODS
  Series of steroid derivatives having pure and potent antagonistic activity on the human and rodent AR were synthesized. Assays of AR binding and activity in carcinoma mouse Shionogi and human LNCaP cells as well as in vivo bioavailability measurements and in vivo prostate weight assays in the rat were used.
  
  
  RESULTS
  The chosen lead steroidal compound, namely EM-5854, has a 3.7-fold higher affinity than BICA for the human AR while EM-5855, an important metabolite of EM-5854, has a 94-fold higher affinity for the human AR compared to BICA. EM-5854 and EM-5855 are 14 times more potent than BICA in inhibiting androgen (R1881)-stimulated prostatic specific antigen (PSA) secretion in human prostatic carcinoma LNCaP cells in vitro. MDV3100 has a potency comparable to bicalutamide in these assays. Depending upon the oral formulation, EM-5854 is 5- to 10-times more potent than BICA to inhibit dihydrotestosterone (DHT)-stimulated ventral prostatic weight in vivo in the rat while MDV3100 has lower activity than BICA in this in vivo model. These data are supported by respective 40-fold and 105-fold higher potencies of EM-5854 and EM-5855 compared to BICA to inhibit cell proliferation in the androgen-sensitive Shionogi carcinoma cell model.
  
  
  CONCLUSIONS
  Although the present preclinical results data need evaluation in clinical trials in men, combination of the data obtained in vitro in human LNCaP cells as indicator of potency in the human prostate and the data on metabolism evaluated in vivo on ventral prostate weight in the rat, could suggest the possibility of a 70- to 140-fold higher potency of EM-5854 compared to bicalutamide (Casodex) for the treatment of prostate cancer in men.
authors.affiliation: Endoresearch Inc., 2989, de la Promenade, Quebec City, QC, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Gauthier
authors.forename: Céline
authors.initials: C
authors.lastname: Martel
authors.forename: Fernand
authors.initials: F
authors.lastname: Labrie
mesh_terms: D059002:Androgen Receptor Antagonists / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000502:physiology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D017430:Prostate-Specific Antigen