Estrogen receptor dependent inhibitors of NF-kappaB transcriptional activation-1 synthesis and biological evaluation of substituted 2-cyanopropanoic acid derivatives: pathway selective inhibitors of NF-kappaB, a potential treatment for rheumatoid arthritis.
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.
Caggiano
Thomas J
TJ
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, New Jersey 08540-8000, USA. caggiat@wyeth.com
Brazzale
Antony
A
Ho
Douglas M
DM
Kraml
Christina M
CM
Trybulski
Eugene
E
Chadwick
Christopher C
CC
Chippari
Sue
S
Borges-Marcucci
Lisa
L
Eckert
Amy
A
Keith
James C
JC
Kenney
Thomas
T
Harnish
Douglas C
DC
D000284:Administration, Oral; D000818:Animals; D030801:Animals, Genetically Modified; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D002460:Cell Line; D003402:Creatine Kinase / Q000378:metabolism; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D008156:Luciferases / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D016328:NF-kappa B; D009570:Nitriles; D011422:Propionates; D008156:Luciferases; D003402:Creatine Kinase