title: 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.
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.
authors.affiliation: GlaxoSmithKline Research and Development, Stevenage, Herts, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Howe
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Mount
authors.forename: Kirsty
authors.initials: K
authors.lastname: Bess
authors.forename: Amy
authors.initials: A
authors.lastname: Brown
authors.forename: Peter
authors.initials: P
authors.lastname: Bungay
authors.forename: Karl R
authors.initials: KR
authors.lastname: Gibson
authors.forename: Tony
authors.initials: T
authors.lastname: Hawcock
authors.forename: Jacques
authors.initials: J
authors.lastname: Richard
authors.forename: Gareth
authors.initials: G
authors.lastname: Jones
authors.forename: Rosalind
authors.initials: R
authors.lastname: Walley
authors.forename: Alison
authors.initials: A
authors.lastname: McLeod
authors.forename: Coralie
authors.initials: C
authors.lastname: Apfeldorfer
authors.forename: Simeon
authors.initials: S
authors.lastname: Ramsey
authors.forename: Sarah
authors.initials: S
authors.lastname: Tweedy
authors.forename: Nick
authors.initials: N
authors.lastname: Pullen
mesh_terms: D000328:Adult; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004715:Endometriosis / Q000188:drug therapy; D004717:Endometrium / Q000187:drug effects*; D004958:Estradiol / Q000097:blood; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D005498:Follicular Phase / Q000187:drug effects*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008251:Macaca; D015735:Mifepristone / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D011720:Pyrazoles / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*; D057170:Translational Research, Biomedical; D055815:Young Adult
chemical_list: C568445:4-(3-cyclopropyl-1-(methylsulfonylmethyl)-5-methyl-1H-pyrazol-4-yl)oxy-2,6-dimethylbenzonitrile; D004968:Estrogens, Non-Steroidal; D006727:Hormone Antagonists; D011720:Pyrazoles; D011980:Receptors, Progesterone; D013450:Sulfones; D015735:Mifepristone; D004958:Estradiol; D007986:Luteinizing Hormone