title: Molecular and pharmacological properties of a potent and selective novel nonsteroidal progesterone receptor agonist tanaproget.
abstract: Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC(50) value of 0.1 nm, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy ( approximately 60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC(50) value of 0.02 nm) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.
authors.affiliation: Women's Health Research Institute, Wyeth Research, Collegeville, Pennsylvania 19426, USA. zhangz@wyeth.com
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Olland
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jeff
authors.initials: J
authors.lastname: Cohen
authors.forename: Tom
authors.initials: T
authors.lastname: Berrodin
authors.forename: Susan
authors.initials: S
authors.lastname: Chippari
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Appavu
authors.forename: Shen
authors.initials: S
authors.lastname: Li
authors.forename: James
authors.initials: J
authors.lastname: Wilhem
authors.forename: Raj
authors.initials: R
authors.lastname: Chopra
authors.forename: Andrew
authors.initials: A
authors.lastname: Fensome
authors.forename: Puwen
authors.initials: P
authors.lastname: Zhang
authors.forename: Jay
authors.initials: J
authors.lastname: Wrobel
authors.forename: Rayomand J
authors.initials: RJ
authors.lastname: Unwalla
authors.forename: C Richard
authors.initials: CR
authors.lastname: Lyttle
authors.forename: Richard C
authors.initials: RC
authors.lastname: Winneker
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D019943:Amino Acid Substitution; D048588:Benzoxazines / Q000819:agonists*; D001665:Binding Sites; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D011397:Promegestone / Q000031:analogs & derivatives / Q000494:pharmacology; D011758:Pyrroles / Q000819:agonists*; D011980:Receptors, Progesterone / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D011994:Recombinant Proteins / Q000819:agonists; D014961:X-Ray Diffraction
chemical_list: D048588:Benzoxazines; D008024:Ligands; D011758:Pyrroles; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; C503890:tanoproget; C050319:trimegestone; D011397:Promegestone; D000469:Alkaline Phosphatase