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项与 Unitech Pharmaceuticals, Inc. 相关的药物

GBL-5b

靶点

Capsid x IL-6 x TNF

作用机制

Capsid抑制剂 [+3]

在研机构-

原研机构

Unitech Pharmaceuticals, Inc.

在研适应症-

非在研适应症

类风湿关节炎

最高研发阶段无进展

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首次获批日期-

100 项与 Unitech Pharmaceuticals, Inc. 相关的临床结果

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0 项与 Unitech Pharmaceuticals, Inc. 相关的专利（医药）

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项与 Unitech Pharmaceuticals, Inc. 相关的文献（医药）

2012-06-01·European Journal of Drug Metabolism and Pharmacokinetics4区 · 医学

Metabolism studies of a small-molecule tumor necrosis factor-alpha (TNF-α) inhibitor, UTL-5b (GBL-5b)

4区 · 医学

Article

作者: Jack Jiang ; Jiajiu Shaw ; Ben Chen ; Brian Shay ; Frederick Valeriote

UTL-5b is an anti-inflammatory and anti-arthritic small-molecule tumor necrosis factor-alpha inhibitor and a structural analogue of the anti-arthritic drug, leflunomide. Leflunomide is known to be metabolized to teriflunomide, but the metabolites of UTL-5b have not been reported. The objective of this study was to investigate whether UTL-5b has a similar metabolic behavior as leflunomide. Preliminary studies showed that when exposed to microsomes in vitro with or without NADPH, UTL-5b disappeared within 30 min. To further investigate the microsomal metabolism, liquid chromatography-ultraviolet (LC-UV) and LC/tandem mass spectrometry (LC-MS/MS) were employed to, respectively, monitor the microsomal metabolites and identify the structure of the metabolites using LC-full scan MS and LC combined with multiple-ion monitoring MS. Fragmentation determination was analyzed by two types of scans: product ion scans and precursor ion scan. The in vitro microsomal treatment of UTL-5b resulted in two major metabolites: 5-methylisoxazole-3-carboxylic acid and 2-chloroaniline. Thus, the in vitro metabolic behavior of UTL-5b appears to be different from that of leflunomide in that the isoxazole ring is cleaved.

American Journal of Biomedical Sciences

Anti-inflammatory and Anti-arthritic Effects of a Novel Leflunomide Analogue, UTL-5b (GBL-5b)

Article

作者: Lee, An-Rong ; Zeng, Dustin ; Chen, Ben ; Wooley, Paul ; Shaw, Jiajiu ; Huang, Wen-Hsin

Rheumatoid arthritis (RA) is a common disease characterized by chronic inflammation and irreversible destruction of articular cartilage and bone. In this report, we examined the anti-inflammatory and anti-arthritic effects of a novel leflunomide analogue, UTL-5b (also known as GBL-5b), for potential RA treatment. Using a carrageenan-induced edema study in rats, UTL-5b exhibited a better anti-inflammatory effect as compared with leflunomide and its metabolite. The chronic efficacy of UTL-5b was examined using type II collagen-induced arthritis (CIA) mouse model. UTL-5b exerted an anti-arthritic effect in a dose-dependant manner with mice given 30 mg/kg exhibiting amelioration of disease early in the trial, but losing statistical significance over time. In contrast, mice treated with 60 mg/kg showed reduced clinical disease parameters early in the trial and these effects were sustained over the ten week trial period. Mechanistic studies indicate that UTL-5b is an inhibitor of TNF-α production in vivo. Oral administration of UTL-5b prior to i.p. injection with lethal dose of lipopolysaccharide (LPS)/D-galactosamine markedly reduced the levels of serum TNF-α and increased survival rates of animals from septic shock-induced death. Acute toxicity study using mice receiving increasing doses of UTL-5b showed that no animals were killed by UTL-5b at 2,000 mg/kg (LD(50) >2,000 mg/kg). Our studies show that UTL-5b represents a novel anti-inflammatory and anti-arthritic agent with potential therapeutic application for RA treatment.

American Journal of Biomedical Sciences

A Novel Leflunomide Analog, UTL-5b (GBL-5b), Suppresses JAK3, MAP3K2, and LITAF Genes

作者: Palfey, Bruce ; Lee, An-Rong ; Huang, Wen-Hsin ; Chen, Ben ; Zeng, Dustin ; Wooley, Paul ; Shaw, Jiajiu

UTL-5b (GBL-5b) is a novel analog of leflunomide with anti-inflammatory and antiarthritic effects.It has been shown to lower serum tumor necrosis factor-alpha (TNF-α) level induced by lipopolysaccharide (LPS) in an animal model.In this study, the effect of UTL-5b on nitric oxide (NO) and dihydroorotate dehydrogenase (DHODH) was investigated.Our in vitro studies showed that (1) UTL-5b is a stronger inhibitor of NO production as compared to leflunomide and its active metabolite, teriflunomide, and (2) Unlike leflunomide, a potent inhibitor of DHODH, UTL-5b does not inhibit DHODH activity.These findings show that UTL-5b acts in a manner different from that of leflunomide.To further investigate the mode of action of UTL-5b, an ex vivo gene array study was performed.C57BL/6 mice were injected s.c. with of UTL-5b 24 h before injection of E. coli LPS.Mice were sacrificed 90 min later and the whole spleen mRNA was isolated for gene microarray anal.The results showed that UTL-5b significantly suppressed three genes that are relevant to the TNF-α pathway: Janus kinase 3 (JAK3), mitogen-activated protein kinase kinase kinase 2 (MAP3K2) and lipopolysaccharide-induced TNF-α factor (LITAF).In summary, our results showed that UTL-5b has a stronger inhibitory effect on NO production than leflunomide; yet, unlike leflunomide, UTL-5b does not inhibit DHODH in vitro.In addition, gene array anal. showed that the biol. effects of UTL-5b are attributed at least in part to the suppression of JAK3, MAP3K2 and LITAF gene expression.

100 项与 Unitech Pharmaceuticals, Inc. 相关的药物交易

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100 项与 Unitech Pharmaceuticals, Inc. 相关的转化医学

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