Salicylanilides: selective inhibitors of interleukin-12p40 production.
Interleukin (IL)-12p40, a subunit component of both IL-12 and IL-23, is being widely studied for its role in inflammatory disease. As part of an effort to profile cellular signaling pathways across different cell types, we report salicylanilide inhibitors of IL-12p40 production in stimulated dendritic cells. Based on a hypothesis that a desirable therapeutic profile is one that could block IL-12p40 but not IL-6 production, we engaged in directed analoging. This resulted in salicylanilides with similar IL-12p40 related potency but enhanced selectivity relative to IL-6 production.
Brown
Michael E
ME
Medicinal Chemistry, Amgen Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Fitzner
Jeffrey N
JN
Stevens
Tracey
T
Chin
Wilson
W
Wright
Clifford D
CD
Boyce
Jim P
JP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001681:Biological Assay; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053759:Interleukin-23 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D012458:Salicylanilides / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
D000893:Anti-Inflammatory Agents; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D015850:Interleukin-6; D012458:Salicylanilides; D000093242:Interleukin-6 Inhibitors; C034596:salicylanilide