title: Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348).
abstract: We have continued to explore the 3,3-dialkyl-5-aryloxindole series of progesterone receptor (PR) modulators looking for new agents to be used in female healthcare: contraception, fibroids, endometriosis, and certain breast cancers. Previously we reported that subtle structural changes with this and related templates produced functional switches between agonist and antagonist properties ( Fensome et al. Biorg. Med. Chem. Lett. 2002, 12, 3487; 2003, 13, 1317 ). We herein report a new functional switch within the 5-(2-oxoindolin-5-yl)-1 H-pyrrole-2-carbonitrile class of compounds. We found that the size of the 3,3-dialkyl substituent is important for controlling the functional response; thus small groups (dimethyl) afford potent PR antagonists, whereas larger groups (spirocyclohexyl) are PR agonists. The product from our optimization activities in cell-based systems and also for kinetic properties in rodents and nonhuman primates was 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-1-methyl-1 H-pyrrole-2-carbonitrile 27 (WAY-255348), which demonstrated potent and robust activity on PR antagonist and contraceptive end points in the rat and also in cynomolgus and rhesus monkeys including ovulation inhibition, menses induction, and reproductive tract morphology.
authors.affiliation: Chemical and Screening Sciences, Biotransformation Division, Drug Safety and Metabolism, Women's Health and Musculoskeletal Biology, and BioResources, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. fensoma@wyeth.com
authors.forename: Andrew
authors.initials: A
authors.lastname: Fensome
authors.forename: William R
authors.initials: WR
authors.lastname: Adams
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Adams
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Berrodin
authors.forename: Jeff
authors.initials: J
authors.lastname: Cohen
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Arthur
authors.initials: A
authors.lastname: Illenberger
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Kern
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Hudak
authors.forename: Michael A
authors.initials: MA
authors.lastname: Marella
authors.forename: Edward G
authors.initials: EG
authors.lastname: Melenski
authors.forename: Casey C
authors.initials: CC
authors.lastname: McComas
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Mugford
authors.forename: Ov D
authors.initials: OD
authors.lastname: Slayden
authors.forename: Matthew
authors.initials: M
authors.lastname: Yudt
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Puwen
authors.initials: P
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Richard C
authors.initials: RC
authors.lastname: Winneker
authors.forename: Jay E
authors.initials: JE
authors.lastname: Wrobel
mesh_terms: D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D015394:Molecular Structure; D010060:Ovulation / Q000187:drug effects; D000078183:Oxindoles; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C529396:5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; D007211:Indoles; D000078183:Oxindoles; D011758:Pyrroles; D011980:Receptors, Progesterone; C022960:2-oxindole; D000469:Alkaline Phosphatase