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

Q1 · MEDICINE

Article

Author: Chadwick, Christopher C. ; Brazzale, Antony ; Eckert, Amy ; Chippari, Sue ; Harnish, Douglas C. ; Borges-Marcucci, Lisa ; Caggiano, Thomas J. ; Keith, James C. ; Kenney, Thomas ; Kraml, Christina M. ; Ho, Douglas M. ; Trybulski, Eugene

Pathway selective ligands of the estrogen receptor inhibit transcriptional activation of proinflammatory genes mediated by NF-kappaB. Substituted 2-cyanopropanoic acid derivatives were developed leading to the discovery of WAY-204688, an orally active, pathway selective, estrogen receptor dependent anti-inflammatory agent. This propanamide was shown to be orally active in preclinical models of inflammatory diseases, such as rheumatoid arthritis, without the proliferative effect associated with traditional estrogens.

01 Dec 2005·ShockQ2 · MEDICINE

THE ACTIVITY OF PATHWAY-SELECTIVE ESTROGEN RECEPTOR LIGANDS IN EXPERIMENTAL SEPTIC SHOCK

Q2 · MEDICINE

Article

Author: Parejo, Nicolas ; Harnish, Douglas C. ; Cristofaro, Patricia ; Chippari, Sue ; Palardy, John E. ; Steffan, Robert J. ; Opal, Steven M. ; Chadwick, Christopher C. ; Keith, James C. Jr. ; Caggiano, Thomas J. ; Jhung, Jhung W.

Estrogen receptors (ER) are widely expressed in multiple genital and nongenital tissues. Upon engagement of these receptors, multiple genes are affected in target tissues via estrogen response elements. Nonsteroidal pathway-selective ER ligands have recently been identified that inhibit NF-kappaB transcriptional activity and are devoid of conventional estrogenic activities on genital tissues. These pathway-selective ligands are potent anti-inflammatory agents in vivo and may prove to be of therapeutic utility in systemic inflammatory states. These pathway-selective ER ligands were tested in the murine listeriosis model, the neutropenic rat model, and the mouse cecal ligation and puncture model. WAY-204688 did not have any significant activity after systemic infection by Listeria monocytogenes. In the neutropenic rat model, WAY-204688 provided a significant survival benefit against an otherwise lethal challenge of Pseudomonas aeruginosa 12.4.4 compared with the control group (88% versus 25% survival; P < 0.05). Preservation of mucosal weight and prevention of histopathologic changes were observed with the administration of WAY-204688. Similar findings were observed in a cecal ligation and puncture model with WAY-204688 and a related compound WAY-169916. These results indicate that oral administration of these pathway-selective ER ligands preserved gastrointestinal barrier function and improve outcome in experimental models of systemic infection and inflammation. These agents may prove to be useful clinically as a novel treatment strategy for severe sepsis.

100 Deals associated with SIM-688

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 1	-	Pfizer Inc.	-
Rheumatoid Arthritis	Phase 1	-	ArQule, Inc.	-
Rheumatoid Arthritis	Phase 1	US	Wyeth Ltd. (India)	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

SIM-688

Overview

Basic Info

Structure/Sequence

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation