title: Inhibition of Toll-like receptor-mediated inflammation in vitro and in vivo by a novel benzoxaborole.
abstract: Pro-inflammatory cytokines play a critical role in the development of autoimmune and inflammatory diseases. Targeting the cytokine environment has proven efficient for averting inflammation. In this study, we reported that 6-[4-(aminomethyl)-2-chlorophenoxyl]benzo[c][1,2]oxaborol-1(3H)-ol (AN3485), a benzoxaborole analog, inhibited TLR2-, TLR3-, TLR4-, and TLR5-mediated TNF-α, IL-1β, and IL-6 release from human PBMCs and isolated monocytes with IC(50) values ranging from 18 to 580 nM, and the inhibition was mediated at the transcriptional level. Topical administration of AN3485 significantly reduced PMA-induced contact dermatitis and oxazolone-induced delayed-type hypersensitivity in mice, indicating its capability of penetrating skin and potential topical application in skin inflammation. Oral administration of AN3485 showed dose-dependent suppression of LPS-induced TNF-α and IL-6 production in mice with an ED(90) of 30 mg/kg. Oral AN3485, 35 mg/kg, twice a day, suppressed collagen-induced arthritis in mice over a 20-day period. The potent anti-inflammatory activity in in vitro and in vivo disease models makes AN3485 an attractive therapeutic lead for a variety of cutaneous and systemic inflammatory diseases.
authors.affiliation: Anacor Pharmaceuticals, 1020 E Meadow Circle, Palo Alto, CA 94303, USA. cdong@anacor.com
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: Holly
authors.initials: H
authors.lastname: Sexton
authors.forename: Ana
authors.initials: A
authors.lastname: Gertrudes
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Akama
authors.forename: Shamra
authors.initials: S
authors.lastname: Martin
authors.forename: Charlotte
authors.initials: C
authors.lastname: Virtucio
authors.forename: Chiao-Wen
authors.initials: CW
authors.lastname: Chen
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Fan
authors.forename: Anne
authors.initials: A
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Bu
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Lisa
authors.initials: L
authors.lastname: Feng
authors.forename: Kurt
authors.initials: K
authors.lastname: Jarnagin
authors.forename: Yvonne R
authors.initials: YR
authors.lastname: Freund
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001168:Arthritis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001896:Boron Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors*
chemical_list: C579257:6-(4-(aminomethyl)-2-chlorophenoxyl)benzo(c)(1,2)oxaborol-1(3H)-ol; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016207:Cytokines; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors