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

David C Howe, Howe DC, David Howe, Natalie Mount, Mount NM, Natalie M Mount, Kirsty Bess, Bess K, Amy Brown, Brown A, Bungay P, Peter J. Bungay, Peter Bungay, Karl R. Gibson, Gibson KR, Hawcock T, Tony Hawcock, Richard J, Jacques Richard, Gareth Jones, Jones G, Walley R, Rosalind Walley, McLeod A, Alison McLeod, Apfeldorfer C, Coralie Apfeldorfer, Coralie S. Apfeldorfer, Ramsey S, Simeon Ramsey, Sarah Tweedy, Tweedy S, Nick Pullen
The Journal of pharmacology and experimental therapeutics · 2011 · vol. 339(2) , pp. 642–653 · doi:10.1124/jpet.111.183848 · PMID:21849626 · W2143472382
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This study evaluated the anti-proliferative effects of PF-02413873, a nonsteroidal progesterone receptor antagonist, on endometrial growth in macaques and humans.

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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, 11β-4-dimethylaminophenyl-17β-hydroxy-17α-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.

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Condition tags

endometriosis

MeSH descriptors

Endometrium Estrogens, Non-Steroidal Follicular Phase Pyrazoles Receptors, Progesterone Sulfones Adult Animals Dose-Response Relationship, Drug Double-Blind Method Endometriosis Endometriosis Endometrium Estradiol Estradiol Estrogens, Non-Steroidal Female Follicular Phase Hormone Antagonists Hormone Antagonists

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