LX-2931(LX-2931) - 药物靶点：SGPL1_在研适应症：胰腺癌，结直肠癌，三阴性乳腺癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

1-(4-((1R,2S,3R)-1,2,3,4-Tetrahydroxybutyl)-1H-imidazol-2-yl) ethanone oxime

+ [4]

靶点

SGPL1

作用机制

SGPL1抑制剂(鞘氨醇-1-磷酸酶-1抑制剂)

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病+ [1]

在研适应症

胰腺癌结直肠癌三阴性乳腺癌

非在研适应症

达里耶病杜氏肌营养不良症类风湿关节炎

原研机构

Lexicon Pharmaceuticals, Inc.

在研机构

AC BioScience SA初创企业

非在研机构

Lexicon Pharmaceuticals, Inc.Dermecular Therapeutics, Inc.

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (欧盟)

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结构

分子式C9H15N3O5

InChIKeyAMXVYJYMZLDINS-RSWLNLDNSA-N

CAS号948840-25-3

关联

6

项与 LX-2931 相关的临床试验

EUCTR2018-000373-80-FR / Not yet recruiting临床1/2期

A Phase 1/2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Study of the Safety and Efficacy of LX3305, a Sphingosine-1-Phosphate Lyase Inhibitor, for Treatment of Darier’s Disease or Hailey-Hailey Disease - DERM-101

开始日期2018-05-24

申办/合作机构

Dermecular Therapeutics, Inc.

NCT01417052 / Completed临床1期

A Phase 1, Single-Center, Randomized, Double-Blind, Placebo-Controlled, Dose Escalation Study to Determine the Safety and Efficacy of Daily Orally Administered LX3305 in Subjects With Active Rheumatoid Arthritis (RA)

The primary objective of this study is to determine the safety of LX3305 in a dose escalation compared with placebo over 12 weeks in subjects with active rheumatoid arthritis (RA).

开始日期2011-09-01

申办/合作机构

Lexicon Pharmaceuticals, Inc.

EUCTR2009-012705-19-BG / Not yet recruitingN/A

A Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled, Multiple-dose Study to Determine the Safety and Efficacy of Daily Orally Administered LX3305 in Subjects with Active Rheumatoid Arthritis (RA) on Stable Methotrexate (MTX) Therapy - LX3305.201

开始日期2009-09-29

申办/合作机构

Lexicon Pharmaceuticals, Inc.

100 项与 LX-2931 相关的临床结果

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100 项与 LX-2931 相关的转化医学

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100 项与 LX-2931 相关的专利（医药）

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8

项与 LX-2931 相关的文献（医药）

2022-09-01·Biomedicine & Pharmacotherapy

In vitro and in vivo pharmacological characterization of dasotraline, a dual dopamine and norepinephrine transporter inhibitor in vivo

Article

作者: Fang, Q Kevin ; Hardy, Larry W ; Lew, Robert ; Quinton, Maria S ; Schreiber, Rudy ; Campbell, Una

Inhibitors of dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) are effective treatments for neuropsychiatric diseases. Dasotraline [(1R,4 S)- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine, also known as SEP-225289) was evaluated for its inhibitory potency at DAT, NET and SERT using in vitro and in vivo assays. In vitro radiometric functional uptake studies showed preferential inhibition by dasotraline of hDAT (IC₅₀ =3 nM) and hNET (IC₅₀ =4 nM relative to hSERT(IC₅₀ =15 nM). In mouse ex vivo occupancy studies, dasotraline demonstrated total plasma concentration-dependent occupancy at DAT, NET and SERT. Determination of the TO₅₀ (50% transporter occupancy) were 32, 109 and 276 ng/ml, respectively. In SPECT imaging studies in baboons, dasotraline (0.2 mg/kg iv) displaced radiotracer binding to DAT by 87% but only 20% at NET and SERT. Rat microdialysis studies were performed in prefrontal cortex and striatum. Dasotraline produced sustained (>4 h) increases in dopamine and norepinephrine concentrations. Dasotraline was also more potent at increasing synaptic dopamine in the striatum, and norepinephrine in the prefrontal cortex than serotonin in these regions. In summary, dasotraline preferentially inhibits DAT and NET relative to SERT. Together, the occupancy and neurochemical profile of dasotraline provide a mechanistic basis for the treatment of diseases that have an underlying causality involving dopamine and norepinephrine dysfunction.

2019-08-01·Bone2区 · 医学

Agonist-induced activation of the S1P receptor 2 constitutes a novel osteoanabolic therapy for the treatment of osteoporosis in mice

2区 · 医学

Article

作者: Manthe, Kristina ; Heusch, Gerd ; Weske, Sarah ; Levkau, Bodo ; von Wnuck Lipinski, Karin ; Vaidya, Mithila ; Burkhart, Christoph ; Haberhauer, Gebhard ; Keul, Petra

BACKGROUND AND PURPOSEOsteoporosis is a worldwide epidemic but pharmacological agents to stimulate new bone formation are scarce. We have shown that increasing tissue levels of sphingosine-1-phosphate (S1P) by blocking its degradation by the S1P lyase has pronounced osteoanabolic effect in mouse osteoporosis models by stimulating osteoblast differentiation through the S1P receptor 2 (S1P2). However, S1P lyase inhibitors have side effects complicating potential clinical use. Here, we tested whether direct S1P2 engagement by the S1P2 agonist CYM5520 exerted osteoanabolic potential in estrogen deficiency-induced osteopenia in mice. We compared its efficacy to LX2931, a novel S1P lyase inhibitor currently tested in rheumatoid arthritis.EXPERIMENTAL APPROACHCYM5520, LX2931 or vehicle were administered to ovariectomized mice for 6 weeks beginning 5 weeks after ovariectomy, Bone mass, cellular composition and mechanical strength were assessed by microCT, histomorphometry and three point bending tests. Plasma markers of bone metabolism were analyzed by ELISA.KEY RESULTSTherapeutic treatment with CYM5520 and LX2931 clearly increased long bone and vertebral bone mass to impressive 3-5 fold over vehicle in osteopenic ovariectomized mice. As expected, lymphopenia was a side effect of LX2931, whereas none occurred with CYM5520. Consistent with an osteoanabolic effect, CYM5520 increased osteoblast number, osteoid surface and alkaline phosphatase area 2-3 fold over vehicle. Plasma concentrations of the osteoanabolic marker procollagen I C-terminal propeptide were also elevated by CYM5520 and LX2931. LX2931 but not yet CYM5520 increased cortical thickness and mechanical strength without affecting mineral density.CONCLUSION AND IMPLICATIONSTreatment with a pharmacological S1P2 agonist corrected ovariectomy-induced osteopenia in mice by inducing new bone formation thus constituting a novel osteoanabolic approach to osteoporosis.

2016-11-01·American Journal of Physiology-Lung Cellular and Molecular Physiology2区 · 医学

Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931

2区 · 医学

Article

作者: Dzyubachyk, Oleh ; Radzioch, Danuta ; Stolarczyk, Marta ; Wojewodka, Gabriella ; Dik, Willem A. ; De Sanctis, Juan B. ; Scholte, Bob J. ; de Kleer, Ismé ; Oravecz, Tamas ; Veltman, Mieke

Progressive lung disease with early onset is the main cause of mortality and morbidity in cystic fibrosis patients. Here we report a reduction of sphingosine-1-phosphate (S1P) in the lung of unchallenged Cftr tm1EUR F508del CFTR mutant mice. This correlates with enhanced infiltration by inducible nitric oxide synthase (iNOS)-expressing granulocytes, B cells, and T cells. Furthermore, the ratio of macrophage-derived dendritic cells (MoDC) to conventional dendritic cells (cDC) is higher in mutant mouse lung, consistent with unprovoked inflammation. Oral application of a S1P lyase inhibitor (LX2931) increases S1P levels in mutant mouse tissues. This normalizes the lung MoDC/cDC ratio and reduces B and T cell counts. Lung granulocytes are enhanced, but iNOS expression is reduced in this population. Although lung LyC6+ monocytes are enhanced by LX2931, they apparently do not differentiate to MoDC and macrophages. After challenge with bacterial toxins (LPS-fMLP) we observe enhanced levels of proinflammatory cytokines TNF-α, KC, IFNγ, and IL-12 and the inducible mucin MUC5AC in mutant mouse lung, evidence of deficient resolution of inflammation. LX2931 does not prevent transient inflammation or goblet cell hyperplasia after challenge, but it reduces MUC5AC and proinflammatory cytokine levels toward normal values. We conclude that lung pathology in homozygous mice expressing murine F508del CFTR, which represents the most frequent mutation in CF patients, is characterized by abnormal behavior of infiltrating myeloid cells and delayed resolution of induced inflammation. This phenotype can be partially corrected by a S1P lyase inhibitor, providing a rationale for therapeutic targeting of the S1P signaling pathway in CF patients.

100 项与 LX-2931 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06297

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
杜氏肌营养不良症	临床2期	美国	Lexicon Pharmaceuticals, Inc.	-
胰腺癌	临床2期	-	AC BioScience SA初创企业	-
类风湿关节炎	临床前	捷克	Lexicon Pharmaceuticals, Inc.	2009-07-01
结直肠癌	临床前	瑞士	AC BioScience SA初创企业	-
达里耶病	药物发现	法国	Dermecular Therapeutics, Inc.	2018-05-24
类风湿关节炎	药物发现	波兰	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	药物发现	美国	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	药物发现	匈牙利	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	药物发现	保加利亚	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	药物发现	塞尔维亚	Lexicon Pharmaceuticals, Inc.	2009-07-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00903383 (CTgov)	临床2期	类风湿关节炎	208	LX3305 low dose (Low Dose)	糧醖築構齋壓廠餘襯膚(餘遞積壓憲獵範醖鑰窪) = 壓餘衊製製醖壓憲簾鑰夢構鬱齋憲夢艱膚構艱 (廠遞網襯鬱遞簾鏇糧鑰, 願觸鹽遞壓壓築鏇築淵 ~ 鹽選衊壓衊鑰淵範鬱壓) 更多	-	2011-12-15
				LX3305 mid dose (Mid Dose)	糧醖築構齋壓廠餘襯膚(餘遞積壓憲獵範醖鑰窪) = 鹽襯壓夢繭蓋壓蓋構遞夢構鬱齋憲夢艱膚構艱 (廠遞網襯鬱遞簾鏇糧鑰, 鏇顧艱憲範齋築獵鹹鹽 ~ 範網獵鬱鹹廠願願醖網) 更多
NCT00847886 (CTgov)	临床1期	类风湿关节炎	15	LX3305+Methotrexate (LX3305 + Methotrexate)	糧齋繭遞膚積鬱製窪艱(廠製蓋鹽淵選糧醖繭醖) = 鹽構憲鑰鏇膚繭憲淵繭醖窪遞艱窪窪齋襯顧遞 (積簾簾製觸膚窪鹽憲廠, 網餘遞齋網鹽憲襯構壓 ~ 獵鏇鬱蓋壓鹹壓觸鹹糧) 更多	-	2010-06-03
				Methotrexate (Methotrexate)	糧齋繭遞膚積鬱製窪艱(廠製蓋鹽淵選糧醖繭醖) = 糧壓繭齋鑰蓋鹽憲糧網醖窪遞艱窪窪齋襯顧遞 (積簾簾製觸膚窪鹽憲廠, 鏇壓蓋鬱夢獵網鑰獵襯 ~ 顧製襯廠襯糧齋齋衊遞) 更多
EULAR2009	临床1期	类风湿关节炎 \| 其他疾病	144	LX2931	(糧遞積壓壓觸製鬱鹽製) = 鑰鹹選鹹構簾積構網膚鑰餘窪廠鏇範製醖鹹簾 (襯簾遞蓋壓觸夢糧膚衊 )	-	2009-06-10