title: Synthesis and biological evaluation of 11' imidazolyl antiprogestins and mesoprogestins.
abstract: Antiprogestins with a 4' para imidazolylphenyl moiety were synthesized and their biochemical interactions with the progesterone and glucocorticoid receptor were investigated. Depending on the substitution pattern at the 17 position partial progesterone receptor (PR)-agonistic derivatives like compounds EC339 and EC336 or pure antagonists like compound EC317 were obtained. EC317 was investigated in vivo and found to be significantly more potent than RU 486 in cycling and pregnant guinea pigs. For testing the biological action progesterone receptor modulators (PRM), guinea pigs appears as a specific model when compare to pregnant human uterus. This model correlates to human conditions such as softening and widening of the cervix, the elevation of the uterine responsiveness to prostaglandins and oxytocin, and finally to induction of labor. The use of non-pregnant guinea pigs permitted the simultaneous assessment of PR-agonistic and PR-antagonistic properties and their physiological interactions with uterine and vaginal environment. These can histologically be presumed from the presence of estrogen or progesterone dominance in the genital tract tissues. The ovarian histology indicated the effects on ovulation. Corpora lutea in guinea pigs further reflects inhibitory effects of the progesterone-dependent uterine prostaglandin secretion. PRMs are initially synthesized as analogues of RU 486. They represent a heterogeneous group of compounds with different ratios of PR-agonistic and-antagonistic properties. PR-agonistic properties may be essential for uterine anti-proliferative effects. In various clinical studies these were also attributed to RU 486 or Ulipristal [1,2]. Adjusted PR-agonistic PRMs (EC312, EC313) [3] may be more effective in achieving a mitotically resting endometrium and superior uterine tumor inhibition. For the use in termination of pregnancy, progesterone-inhibitory effects are essentially needed. Even minor PR-agonistic properties compromise the therapeutic goals. Pure PR-antagonists, as EC317, clearly exceeded the gold standard RU 486 with respect to labor inducing effects. Mechanistically it is surprising that both types of compound may be potent inhibitors of ovulation.
authors.affiliation: Evestra, Inc., San Antonio, TX, USA. Electronic address: knickisch@evestra.com.
authors.forename: Klaus
authors.initials: K
authors.lastname: Nickisch
authors.affiliation: Evestra, Inc., San Antonio, TX, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Elger
authors.affiliation: Evestra, Inc., San Antonio, TX, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Santhamma
authors.affiliation: St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Garfield
authors.affiliation: St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Killeen
authors.affiliation: Leibnitz Institute for Zoological- and Wildlife Research, IZW, Berlin, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Amelkina
authors.affiliation: Evestra, Inc., San Antonio, TX, USA.
authors.forename: Birgitt
authors.initials: B
authors.lastname: Schneider
authors.affiliation: Beuth University of Applied Science, Berlin, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Meister
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D006168:Guinea Pigs; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011247:Pregnancy; D011374:Progesterone / Q000037:antagonists & inhibitors; D011372:Progestins / Q000037:antagonists & inhibitors; D014599:Uterus / Q000187:drug effects
chemical_list: D006727:Hormone Antagonists; D011372:Progestins; D015735:Mifepristone; D011374:Progesterone
keywords: Antiprogestins; Cervix widening; Postcoital fertility control