Estrogen receptor dependent inhibitors of NF-κB transcriptional activation-1 synthesis and biological evaluation of substituted 2-cyanopropanoic acid derivatives: Pathway selective inhibitors of NF-κB, a potential treatment for rheumatoid arthritis

Journal of Medicinal Chemistry

Volumn 50, Issue 22, 2007, Pages 5245-5248

  Caggiano, Thomas J ^a   Brazzale, Antony ^a   Ho, Douglas M ^b   Kraml, Christina M ^a   Trybulski, Eugene ^a   Chadwick, Christopher C ^a   Chippari, Sue ^a   Borges Marcucci, Lisa ^a   Eckert, Amy ^a   Keith, James C ^a   Kenney, Thomas ^a   Harnish, Douglas C ^a  

^a PFIZER INC   (United States)

^b PRINCETON UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 CYANO 3,3 DINAPHTHALEN 1 YLPROPIONIC ACID ETHYL ESTER; 2 CYANOPROPANOIC ACID DERIVATIVE; ANTIINFLAMMATORY AGENT; ESTROGEN RECEPTOR; FUNCTIONAL GROUP; I KAPPA B; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; NITRILE; PROPIONAMIDE DERIVATIVE; PROPIONIC ACID DERIVATIVE; SIM 688; UNCLASSIFIED DRUG; WAY 204688;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; C57BL 6 MOUSE; CONTROLLED STUDY; DRUG MECHANISM; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; GENE ACTIVATION; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; INFLAMMATION; INFLAMMATORY DISEASE; LIGAND BINDING; NONHUMAN; RHEUMATOID ARTHRITIS; STEREOCHEMISTRY; SUBSTITUTION REACTION; TRANSCRIPTION INITIATION;

ADMINISTRATION, ORAL; ANIMALS; ANIMALS, GENETICALLY MODIFIED; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTIRHEUMATIC AGENTS; ARTHRITIS, EXPERIMENTAL; CELL LINE; CREATINE KINASE; CRYSTALLOGRAPHY, X-RAY; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; HUMANS; INFLAMMATORY BOWEL DISEASES; LUCIFERASES; MICE; NF-KAPPA B; NITRILES; PROPIONIC ACIDS; RATS; RATS, INBRED LEW; RATS, SPRAGUE-DAWLEY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TRANS-ACTIVATION (GENETICS);

EID: 35848936345     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm701013k     Document Type: Article

References (23)

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17. A discussion of the synthesis and SAR of this series is beyond the scope of this Letter and will be the subject of a separate report.
18. (2S)-3-[4-(3-Chloro-2-methylphenyl)piperazin-1-yl]-2-[(S) -(2-meth-oxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile.
19. (2S,3S)-3-(2-Methoxyphenyl)-2-methyl-3-(1-naphthyl) -2-({4-[3-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)propanenitrile.
20. AIA model: 12 week old ovariectomized female Lewis rats were injected with Freund's adjuvant. After 8 days, inflammation is established and the animals are dosed for 16 days with the test compound. The hindpaw joint is monitored and scored for swelling and erythema (1-3 scale; max = 12). Tissue is collected for histology scoring (synovial hyperplasia, inflammatory cell infiltration, pannus formation, and articular cartilage destruction).
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