title: Molecular properties and preclinical pharmacology of JNJ-1250132, a steroidal progesterone receptor modulator that inhibits binding of the receptor to DNA in vitro.
abstract: Progesterone receptor modulators have diverse potential therapeutic uses, including the treatment of endometriosis, uterine fibroids and breast cancer. Here we describe the molecular properties and preclinical pharmacology of a new steroidal progestin antagonist, JNJ-1250132. The compound is a high affinity ligand for the progesterone receptor, possessing cross-reactivity with other steroid receptors comparable to that of steroidal antagonists such as mifepristone. It inhibits progestin-inducible alkaline phosphatase gene expression in T47D human breast cancer cells, and also inhibits their in vitro proliferation. It inhibits gestation in rats and progesterone-dependent endometrial transformation in rabbits with efficacies comparable to mifepristone. Like mifepristone, it is a glucocorticoid antagonist in vivo. In cell-free DNA binding assays, the compound inhibits binding of the human progesterone receptor to a progesterone response element, and thus is similar to onapristone in this regard. In contrast, as judged by proteolytic analysis, JNJ-1250132 induces a receptor conformation more similar to that induced by mifepristone, which promotes receptor binding to DNA. Therefore, JNJ-1250132 has unique effects on the progesterone receptor that may translate into a novel clinical profile.
authors.affiliation: Department of Reproductive Therapeutics, Johnson & Johnson Pharmaceutical Research and Development, 1000 US Route, 202 South, P.O. Box 300, Raritan, NJ 08869, USA. gallan@prdus.jnj.com
authors.forename: George F
authors.initials: GF
authors.lastname: Allan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Palmer
authors.forename: Amy
authors.initials: A
authors.lastname: Musto
authors.forename: Muh-Tsann
authors.initials: MT
authors.lastname: Lai
authors.forename: Joanna
authors.initials: J
authors.lastname: Clancy
authors.forename: Stephen
authors.initials: S
authors.lastname: Palmer
mesh_terms: D000818:Animals; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006067:Gonanes / Q000378:metabolism; D006727:Hormone Antagonists / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015735:Mifepristone / Q000378:metabolism / Q000494:pharmacology; D011372:Progestins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D006067:Gonanes; D006727:Hormone Antagonists; D011372:Progestins; D011980:Receptors, Progesterone; D013256:Steroids; D015735:Mifepristone; D004247:DNA; C053238:onapristone; C513607:JNJ-1250132