title: Characterization of a new class of selective nonsteroidal progesterone receptor agonists.
abstract: The identification of a new series of selective nonsteroidal progesterone receptor (PR) agonists is reported. Using a high-throughput screening assay based on the measurement of transactivation of a mouse mammary tumor virus promoter-driven luciferase reporter (MMTV-Luc) in human breast cancer T47D cells, a benzimidazole-2-thione analog was identified. Compound 1 showed an apparent EC50 of 53 nM and efficacy of 93% with respect to progesterone. It binds to PR with high affinity (Ki nM), but had no or very low affinity for other steroid hormone receptors. Structure-activity relationship studies of a series of benzimidazole-2-thione analogs revealed critical positions for high PR binding affinity and transactivation potency as well as receptor selectivity, as exemplified by 25. Compound 25 binds to human PR with high affinity (Ki nM) and had at least > 1000-fold selectivity for PR versus other steroid receptors. Molecular modeling studies suggested that these agonists overlap favorably with progesterone in the ligand-binding domain of PR. In T47D cells, compound 25 acted as a full agonist in the MMTV-Luc reporter assay, as well as in the induction of endogenous alkaline phosphatase activity with apparent EC50 values of 4 and 9 nM, respectively. In the immature rat model, compound 25 provided a significant suppression of estrogen-induced endometrium hypertrophy as measured by luminal epithelial height. In contrast, compound 25 was inactive in the luteinizing hormone release assay in young ovariectomized rats. These benzimidazole-2-thione analogs constitute a new series of nonsteroidal PR agonists with an excellent steroid receptor selectivity profile. The differential activities observed in the in vivo progestogenic assays in rat models suggest that these analogs can act as selective PR modulators.
authors.affiliation: Department of Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, NJ 08543, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Dong
authors.forename: Jacques Y
authors.initials: JY
authors.lastname: Roberge
authors.forename: Zhaoqing
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Joseph
authors.initials: J
authors.lastname: Tamasi
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dell
authors.forename: Rajasree
authors.initials: R
authors.lastname: Golla
authors.forename: James R
authors.initials: JR
authors.lastname: Corte
authors.forename: Yalei
authors.initials: Y
authors.lastname: Liu
authors.forename: Tianan
authors.initials: T
authors.lastname: Fang
authors.forename: Monique N
authors.initials: MN
authors.lastname: Anthony
authors.forename: Dora M
authors.initials: DM
authors.lastname: Schnur
authors.forename: Michele L
authors.initials: ML
authors.lastname: Agler
authors.forename: John K
authors.initials: JK
authors.lastname: Dickson
authors.forename: R Michael
authors.initials: RM
authors.lastname: Lawrence
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Prack
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Jean H M
authors.initials: JH
authors.lastname: Feyen
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: C495120:1-cyclopentyl-6-imidazol-1-yl-1h-benzoidazole-2-thiol-hydrochloride; C495119:6-imidazol-1-isopropyl-1h-benzoimidazole-2-thiol; D001562:Benzimidazoles; D007093:Imidazoles; D011980:Receptors, Progesterone; D013438:Sulfhydryl Compounds; D011374:Progesterone; D007986:Luteinizing Hormone; D017258:Medroxyprogesterone Acetate