Uterine
leiomyomas are highly prevalent and often symptomatic, but current medical
therapies are limited. A novel, potent, selective, orally active
therapy is needed. The goal of these studies was to determine the
progesterone receptor (PR) specificity and activation, endometrial response, and impact on
leiomyoma cell proliferation and extracellular matrix (ECM) production of the novel non-steroidal selective
progesterone receptor modulators (SPRMs)
CP8863 and
CP8947. In vitro progestational activity was assessed by
alkaline phosphatase assay and ER-α expression. In vivo progestational activity was assayed by the McPhail assay. Proliferation and gene expression studies were performed in immortalized human
leiomyoma and myometrial cells. Both
CP8863 and
CP8947 were highly selective for
progesterone receptor (PR) but not for ER-α, AR, and GR. Both compounds induced
alkaline phosphatase comparably to
progesterone, while
CP8947 induced ER-α in
leiomyoma cells but not myometrial cells.
CP8947 was progestational in rabbit endometrium. Nanomolar
CP8947 treatment inhibited human
leiomyoma but not myometrial cell proliferation. Extracellular matrix components were decreased in
leiomyoma cells, including COL1A1 and COL7A1 at nanomolar concentrations.
CP8947 was a potent novel non-steroidal SPRM that was selective for PR, demonstrated progestational activity in endometrium, inhibited
leiomyoma cell proliferation and decreased ECM component production, without disrupting myometrial cell proliferation.