Synthesis and activity of substituted 4-(indazol-3-yl)phenols as pathway-selective estrogen receptor ligands useful in the treatment of rheumatoid arthritis

Journal of Medicinal Chemistry

Volumn 47, Issue 26, 2004, Pages 6435-6438

  Steffan, Robert J ^a   Matelan, Edward ^a   Ashwell, Mark A ^a,c   Moore, William J ^a   Solvibile, William R ^a   Trybulski, Eugene ^a   Chadwick, Christopher C ^a,b   Chippari, Susan ^a   Kenney, Thomas ^a   Eckert, Amy ^a   Borges Marcucci, Lisa ^a   Keith, James C ^a   Xu, Zhang ^a   Mosyak, Lydia ^a   Harnish, Douglas C ^a  

^a PFIZER INC   (United States)

^b Life Diagnostics Inc   (United States)

^c ARQULE INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (INDAZOL 3 YL)PHENOL DERIVATIVE; ESTROGEN RECEPTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LIGAND; PHENOL DERIVATIVE; UNCLASSIFIED DRUG; WAY 169916;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; COMPLEX FORMATION; CONTROLLED STUDY; DRUG ACTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; FEMALE; GENE EXPRESSION; HUMAN; HUMAN CELL; MOUSE; NONHUMAN; RAT; RHEUMATOID ARTHRITIS; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ARTHRITIS, EXPERIMENTAL; ARTHRITIS, RHEUMATOID; CELL LINE; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; HUMANS; INDAZOLES; LIGANDS; MICE; MICE, INBRED C57BL; MODELS, MOLECULAR; NF-KAPPA B; PHENOLS; RATS; RATS, INBRED LEW; RECEPTORS, ESTROGEN; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 10644277062     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049194+     Document Type: Article

References (14)

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11. Ovariectomized C57BL/6 mice (16-20 g) (Taconic) were separated into groups of eight. The mice were fed a chow diet or an atherogenic diet (15.75% fat, 1.25% cholesterol, and 0.5% sodium cholate). EE or test compound was administered once daily by gavage in a methylcellulose/Tween vehicle (0.1 mL per mouse) for 5 weeks. At the end of the experimental period, the liver was collected and uterine wet weight was recorded.
12. Liver total RNA was prepared by using Trizol reagent (BRL). Estrogen and compound regulation of NF-κ target genes were verified by real time RT-PCR using an ABI PRISM 7700 Sequence Detection System according to the manufacturer's protocol (Applied Biosystems). The data were analyzed using the Sequence Detector v1.7 software (Applied Biosystems) and normalized to GAPDH using the Applied Biosystems primer set.
13. Keith, J. C.; Albert, L.; Leatherby, Y, Follettie, M.; Wang, L.; Borges-Marcucci, L.; Chadwick, C. C.; Steffan, R. J.; Harnish, D. C. The Identification of Pathway Selective Estrogen Receptor Ligands Which Inhibit NF-kB Transcriptional Activity and Their Utility in RA. Arthritis Res. Ther., submitted.
14. AIA model: 12 week old ovariectomized female Lewis rats were injected with Freund's Adjuvant. After the joints were inflamed, typically after 8 days, the animals were dosed each day with test compound and monitored to determine hindpaw joint score (erythema and swelling; 0-3 score) max. = 12. Tissue was collected for histology which included synovial hyperplasia, inflammatory cell infiltration, pannus formation, and articular cartilage destruction.