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
| العنوان: | 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 |
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| المؤلفون: | Gareth Jones, Jacques Richard, Simeon Ramsey, Rosalind Walley, Karl Richard Gibson, David C. Howe, Coralie S. Apfeldorfer, Natalie M. Mount, Amy N Brown, Nicholas Pullen, Tony Hawcock, Kirsty Bess, Alison McLeod, Peter M. Bungay, Sarah Tweedy |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 339:642-653 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Adult, medicine.medical_specialty, Endometriosis, Biology, Pharmacology, Endometrium, Hormone antagonist, Translational Research, Biomedical, Young Adult, Hormone Antagonists, Double-Blind Method, Internal medicine, Follicular phase, Progesterone receptor, medicine, Animals, Humans, Estrogens, Non-Steroidal, Molecular Targeted Therapy, Sulfones, Receptor, Dose-Response Relationship, Drug, Estradiol, Antagonist, Mifepristone, Luteinizing Hormone, medicine.anatomical_structure, Endocrinology, Follicular Phase, Macaca, Pyrazoles, Molecular Medicine, Female, Receptors, Progesterone, Luteinizing hormone, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1521-0103 0022-3565 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cf2424928f5d7c154555b10bc8fec040 https://doi.org/10.1124/jpet.111.183848 |
| رقم الأكسشن: | edsair.doi.dedup.....cf2424928f5d7c154555b10bc8fec040 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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