The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

Abstract

There is considerable ongoing investment in the research and development of selective progesterone receptor (PR) modulators for the treatment of gynecological conditions such as endometriosis. Here, we provide the first report on the clinical evaluation of a nonsteroidal progesterone receptor antagonist 4-[3-cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873) in healthy female subjects. In in vitro assays, PF-02413873 behaved as a selective and fully competitive PR antagonist, blocking progesterone binding and PR nuclear translocation. The pharmacological mode of action of PF-02413873 seems to differ from the founding member of the class of steroidal PR antagonists, 11␤-4-dimethylaminophenyl-17␤-hydroxy-17␣-propinyl-4,9-estradiene-3-one (RU-486; mifepristone). Exposure-effect data from studies in the cynomolgus macaque, however, demonstrated that PF-02413873 reduced endometrial functionalis thickness to a comparable degree to RU-486 and this effect was accompanied by a decrease in proliferation rate (as measured by bromodeoxyuridine incorporation) for both RU-486 and high-dose PF-02413873. These data were used to underwrite a clinical assessment of PF-02413873 in a randomized, double-blinded, third-party open, placebo-controlled, dose-escalation study in healthy female volunteers with dosing for 14 days. PF-02413873 blocked the follicular phase increase in endometrial thickness, the midcycle lutenizing hormone surge, and elevation in estradiol in a dose-dependent fashion compared with placebo. This is the first report of translational efficacy data with a nonsteroidal PR antagonist in cynomolgus macaque and human subjects.

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

“…These data are consistent with other non-steroidal PRAs that have been assessed, such as WAY-255348 (Fensome et al, 2008). More recently, PF-02413873 a more potent PRA than PF-02367982 (Table 1) has been shown to reduce endometrial cell proliferation and thickness in intact macaques dosed for 10 days from the start of menstruation (Howe et al, 2011). In this study, however, AR expression was not appreciably altered with PF-02413873 treatment compared with RU-486.…”

“…In contrast to the relatively large wealth or reported data with steroidal PRAs, there is only a single study evaluating the effects of a non-steroidal PRA, PF-02413873, in healthy female subjects (Howe et al, 2011). When orally dosed to healthy female volunteers, daily from the first day of the menstrual cycle, PF-02413873 blocked the mid-cycle LH surge and endometrial growth (Figure 3).…”

“…The pharmacological profile of the non-steroidal compounds appears to be subtly different from steroidal examples (Howe et al, 2011;Zhang et al, 2007). In vitro pharmacological profiling of PRA-910 and PF-02413873 has indicated that at low concentrations the compounds inhibit the expression of progesterone-reporter genes, but at high concentrations, they induce agonism.…”

“…3. Effect of escalating multiple dose of PF-02413873 on endometrial thickness (mm) (a) and the mid cycle LH surge (mIU/mL) (b) in healthy women compared with placebo (Howe et al, 2011) …”

Endometriosis — insights into a multifaceted entity

“…Another approach is to modulate ER activity, either by ER-b ligands (CLI or OBHS) already used in clinical practice [261] or by selective ER modulators (arzoxifene, bazedoxifene [262], raloxifene [263]) which are still tested in experimental models. In the regulation of progesterone action, P4 antagonists (mifepristone, RU-486 [264]) and selective PR modulators (asoprisnil, BAY 1002670) [265], PF-02413873 [266]) have shown promising results in endometriosis therapy in either clinical application or in rodent experiments. In order to eliminate the systemic side effects, Mirena coil (levonorgestrel-releasing intrauterine system) has been added to the therapy [267].…”