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).
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.
Fensome
Andrew
A
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
Adams
William R
WR
Adams
Andrea L
AL
Berrodin
Tom J
TJ
Cohen
Jeff
J
Huselton
Christine
C
Illenberger
Arthur
A
Kern
Jeffrey C
JC
Hudak
Valerie A
VA
Marella
Michael A
MA
Melenski
Edward G
EG
McComas
Casey C
CC
Mugford
Cheryl A
CA
Slayden
Ov D
OD
Yudt
Matthew
M
Zhang
Zhiming
Z
Zhang
Puwen
P
Zhu
Yuan
Y
Winneker
Richard C
RC
Wrobel
Jay E
JE
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
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