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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 1, 2008; DOI: 10.1124/jpet.108.140467

0022-3565/08/3271-78-87$20.00
JPET 327:78-87, 2008
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ENDOCRINE AND DIABETES

The Translational Pharmacology of a Novel, Potent, and Selective Nonsteroidal Progesterone Receptor Antagonist, 2-[4-(4-Cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982)Formula

Alexander de Giorgio-Miller, Peter Bungay, Michelle Tutt, Julie Owen, David Goodwin, and Nick Pullen

Pfizer Global Research and Development, Sandwich, Kent, United Kingdom

The progesterone receptor (PR) is an important regulator of endometrial function. Blockade of PR function has been recognized as the potential basis for preventing gynecological conditions such as endometriosis and uterine fibroids. In this study, we examine the in vitro and in vivo properties of a nonsteroidal PR antagonist, 2-[4-(4-cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982) in comparison with the nonselective steroidal antagonist RU-486 (mifepristone). PF-02367982 was found to be a potent PR antagonist with far greater selectivity over the glucocorticoid receptor than RU-486. Both PF-02367982 and RU-486 blocked progesterone-induced arborization of the rabbit endometrium in a dose-dependent manner at unbound drug exposures that were commensurate with their potencies as PR antagonists in vitro. Translation of this pharmacology to a clinically relevant system was required to bridge the pharmacological gap between nonmenstruating rabbits and humans. Thus, the pharmacokinetic (PK) and pharmacodynamic (PD) data from the rabbit were combined to predict pharmacological effects on the naturally cycling cynomolgus macaque endometrium. PF-02367982 blocked the effect of progesterone on the cynomolgus macaque endometrium to the same degree as RU-486 and at exposures predicted by the rabbit PK-PD model. With such an efficacious and superior selectivity profile to the nonselective RU-486, PF-02367982 may have significant therapeutic value in the treatment of gynecological conditions such as endometriosis.

Received May 1, 2008; accepted June 30, 2008.

Address correspondence to: Dr. Nick Pullen, Pfizer PGRD, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK. E-mail: nick.pullen{at}pfizer.com






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