Inhibition of Toll-Like Receptor-Mediated Inflammation In Vitro and In Vivo by a Novel Benzoxaborole

被引：12

作者：

Dong, Chen ^{[1
]}

Sexton, Holly ^{[1
]}

Gertrudes, Ana ^{[1
]}

Akama, Tsutomu ^{[1
]}

Martin, Shamra ^{[1
]}

Virtucio, Charlotte ^{[1
]}

Chen, Chiao-Wen ^{[1
]}

Fan, Xiaoqin ^{[1
]}

Wu, Anne ^{[1
]}

Bu, Wei ^{[1
]}

Liu, Liang ^{[1
]}

Feng, Lisa ^{[1
]}

Jarnagin, Kurt ^{[1
]}

Freund, Yvonne R. ^{[1
]}

机构：

[1] Anacor Pharmaceut Inc, Palo Alto, CA 94303 USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2013年 / 344卷 / 02期

关键词：

COLLAGEN-INDUCED ARTHRITIS; NF-KAPPA-B; INNATE IMMUNITY; RHEUMATOID-ARTHRITIS; STRUCTURAL BASIS; TNF-ALPHA; TRANSCRIPTION FACTORS; TOPICAL APPLICATION; TLR4-MD-2; COMPLEX; CRYSTAL-STRUCTURE;

D O I：

10.1124/jpet.112.200030

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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-alpha, IL-1 beta, and IL-6 release from human PBMCs and isolated monocytes with IC50 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-alpha and IL-6 production in mice with an ED90 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.

引用

页码：436 / 446

页数：11

共 54 条

[1] Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis [J].