BMS-587101
目录号 : GC62872BMS-587101 是一种有效的具有口服活性的 leukocyte function associated antigen-1 (LFA-1) 拮抗剂。BMS-587101 具有抗炎作用,可用于类风湿关节炎的研究。
Cas No.:509083-77-6
Sample solution is provided at 25 µL, 10mM.
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BMS-587101 is a potent and orally active antagonist of leukocyte function associated antigen-1 (LFA-1). BMS-587101 has anti-inflammatory effects and can be used for rheumatoid arthritis research[1][2].
BMS-587101 is a moderately potent inhibitor of LFA-1-mediated T-cell proliferation, with an IC50 of 20 nM in human HUVEC cells. BMS-587101 inhibits LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production[1][2]. In mouse splenocytes and a mouse ICAM-1 expressing cell lines, bEND, BMS-587101 shows inhibitory activities, with an IC50 of 150 nM[1].
In the mouse ovalbumin-induced lung inflammation model, BMS-587101 (0.1 mg/kg, 1.0 mg/kg, and 10 mg/kg; po.; twice a day) treatment significantly inhibits eosinophil accumulation[1].
[1]. Dominique Potin, et al. Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)--a small molecule antagonist of leukocyte function associated antigen-1. J Med Chem. 2006 Nov 30;49(24):6946-9.
[2]. Suzanne J Suchard, et al. An LFA-1 (alphaLbeta2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis. J Immunol. 2010 Apr 1;184(7):3917-26.
Cas No. | 509083-77-6 | SDF | |
分子式 | C26H20Cl2N4O4S | 分子量 | 555.43 |
溶解度 | DMSO : 260 mg/mL (468.11 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)--a small molecule antagonist of leukocyte function associated antigen-1
J Med Chem 2006 Nov 30;49(24):6946-9.PMID:17125246DOI:10.1021/jm0610806.
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.
An LFA-1 (alphaLbeta2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis
J Immunol 2010 Apr 1;184(7):3917-26.PMID:20190141DOI:10.4049/jimmunol.0901095.
LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.
Metabolite generation via microbial biotransformations with Actinomycetes: rapid screening for active strains and biosynthesis of important human metabolites of two development-stage compounds, 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101) and dasatinib
Drug Metab Dispos 2008 Apr;36(4):721-30.PMID:18227141DOI:10.1124/dmd.107.019570.
The enzymes present in many microbial strains are capable of carrying out a variety of biotransformations when presented with drug-like molecules. Although the enzymes responsible for the biotransformations are not well characterized, microbial strains can often be found that produce metabolites identical to those found in mammalian systems. However, traditional screening for microbial strains that produce metabolites of interest is done with many labor intensive steps that include multiple shake flasks and many manual manipulations, which hinder the application of these techniques in drug metabolite preparation. A 24-well microtiter plate screening system was developed for rapid screening of actinomycetes strains for their ability to selectively produce metabolites of interest. The utility of this system was first demonstrated with the well characterized cytochrome P450 substrate diclofenac. Subsequently, the use of this system allowed the rapid identification of several actinomycetes strains that were capable of converting two drug candidates under development, 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non7-yl-methyl]-3-thiophenecarboxylic acid and N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, Sprycel, BMS-345825), to mammalian metabolites of interest. Milligram quantities of the metabolites were then prepared by scaling-up the microbial biotransformation reactions. These quantities were sufficient for initial characterization, such as testing for pharmacological activity and use as analytical standards, prior to the availability of authentic chemically synthesized compounds.