Received for publication May 1, 2008.
Revised June 30, 2008.
Accepted for publication June 30, 2008.

The Translational Pharmacology Of A Novel, Potent And Selective Non-steroidal Progesterone Receptor Antagonist, PF-02367982

Abstract

The progesterone receptor (PR) is an important regulator of endometrial function. Blockade of PR function has been recognised as the potential basis for preventing gynaecological conditions such as endometriosis and uterine fibroids. Here we examine the in vitro and in vivo properties of a non-steroidal PR antagonist, PF-02367982 in comparison with the non-selective steroidal antagonist RU-486 (mifepristone). PF-02367982 was found to be a potent PR antagonist with far greater selectivity over the glucocorticoid receptor (GR) than RU-486. Both PF-02367982 and RU-486 blocked progesterone-induced arborisation 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 non-menstruating rabbits and human. 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 non-selective RU-486, PF-02367982 may have significant therapeutic value in the treatment of gynaecological conditions such as endometriosis.

Key words: PF-02367982, PK/PD model, PR antagonist, RU-486, endometrium, progesterone