PF-02413873 is a potent, selective, nonsteroidal antagonist of the progesterone receptor (PR). It is identified by CAS 936345-35-6 and has the molecular formula C18H21N3O3S. Its pyrazole-based scaffold distinguishes it from steroidal PR antagonists such as mifepristone and provides a separate chemotype for comparing receptor pharmacology.
Its preclinical and early clinical data support research on receptor competition, endometrial responses, reproductive hormone feedback, and translation across species.
Application of PF-02413873
PF-02413873 supports progesterone-binding and functional assays, receptor-translocation studies, reproductive endocrinology models, and pharmacokinetic comparisons. It enables direct comparison with steroidal PR antagonists.
Relevant endpoints include progesterone-responsive transcription, endometrial thickness, cell proliferation, luteinizing hormone (LH), estradiol, and clearance. Together, they connect target engagement with tissue and endocrine responses. Short-term pharmacodynamic effects should not be interpreted as therapeutic efficacy.
In Vitro
PF-02413873 acts as a selective, fully competitive PR antagonist, with a reported binding Ki of 2.6 nM and a derived Ki of 9.7 nM in a native T47D functional assay; it blocks progesterone binding and PR nuclear translocation and shows a pharmacological profile distinct from that of mifepristone.
Microsomal, hepatocyte, and recombinant CYP studies revealed species-dependent metabolism. CYP3A4 showed the highest turnover among the human CYP enzymes tested.
In Vivo
In cynomolgus macaques, oral Pfizer PF-02413873 reduced endometrial functionalis thickness comparably to mifepristone, while high-dose treatment decreased proliferation. Clearance differed substantially between rats and dogs, consistent with the in vitro metabolism data.
In a randomized, placebo-controlled dose-escalation study, healthy female volunteers received the compound for 14 days. Treatment dose-dependently limited the follicular-phase increase in endometrial thickness, the midcycle LH surge, and the estradiol rise. This demonstrates short-term pharmacodynamic activity, not efficacy in a gynecological disease.
Biochemical and Physiological Actions
The PF-02413873 molecular structure competes with progesterone at the PR ligand-binding domain and changes receptor-dependent transcription. Its fully competitive antagonism and inhibition of PR nuclear translocation distinguish its pharmacological profile from that of mifepristone.
Progesterone promotes secretory differentiation of the endometrium after estrogen-driven proliferation. PR antagonism disrupts this signaling, while changes in LH and estradiol indicate effects on reproductive endocrine feedback. Uterine and hypothalamic-pituitary-ovarian contributions depend on the model and dosing schedule.
Features and Benefits of PF-02413873
- Defined PF-02413873 chemical structure with a nonsteroidal pyrazole-oxybenzonitrile scaffold.
- PF-02413873 molecular weight of 359.44 g/mol for the formula C18H21N3O3S.
- Nanomolar affinity and fully competitive PR antagonism.
- Oral activity evaluated in macaques and healthy volunteers.
- Useful endpoints for receptor, endometrial, endocrine, and translational studies.
Powered by Bioz