ABSTRACT
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.
Subject(s)
Antirheumatic Agents/chemical synthesis , Estrogen Receptor alpha/physiology , Estrogen Receptor beta/physiology , NF-kappa B/antagonists & inhibitors , Nitriles/chemical synthesis , Propionates/chemical synthesis , Administration, Oral , Animals , Animals, Genetically Modified , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antirheumatic Agents/chemistry , Antirheumatic Agents/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Cell Line , Creatine Kinase/metabolism , Crystallography, X-Ray , Estrogen Receptor alpha/genetics , Estrogen Receptor beta/genetics , Humans , Inflammatory Bowel Diseases/drug therapy , Luciferases/genetics , Mice , NF-kappa B/biosynthesis , NF-kappa B/genetics , Nitriles/chemistry , Nitriles/pharmacology , Propionates/chemistry , Propionates/pharmacology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transcriptional ActivationABSTRACT
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.
