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

作用方式

抑制剂

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

非在研机构

Lexicon Pharmaceuticals, Inc.Dermecular Therapeutics, Inc.

权益机构-

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/序列

分子式C9H15N3O5

InChIKeyAMXVYJYMZLDINS-RSWLNLDNSA-N

CAS号948840-25-3

关联

5

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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10

项与 LX-2931 相关的文献（医药）

2025-05-01·Neurobiology of Disease

Dual action of sphingosine 1-phosphate pathway in in vitro models of global cerebral ischemia

Article

作者: Mazzantini, Costanza ; Pellegrini-Giampietro, Domenico E ; Venturini, Martina ; Pugliese, Anna Maria ; Cencetti, Francesca ; Santalmasi, Clara ; Lana, Daniele ; Mulas, Gloria ; Magni, Giada ; Landucci, Elisa ; Bruni, Paola

It is well accepted that sphingolipids play an important role in the pathological process of cerebral ischemia. In the present study we have investigated the involvement of sphingosine 1-phosphate (S1P) pathway in two different in vitro models of global ischemia. In organotypic hippocampal slices exposed to oxygen and glucose deprivation (OGD) we evaluated the mRNA expression of S1P metabolic enzymes and receptors (S1P_1-5) by Real Time-PCR. In the same model we investigated the effect of the inhibitor of S1P lyase (SPL), LX2931, the selective antagonists of S1P₂, JTE-013, and S1P₃, CAY10444, quantifying the cell death in the CA1 region by propidium iodide fluorescence, and morphological and tissue organization alterations by immunohistochemistry and confocal microscopy. Moreover, we performed extracellular recordings of field excitatory postsynaptic potentials in acute slices exposed to OGD. In organotypic slices OGD induced a significant increase of SPL at mRNA level and of S1P₂ and S1P₃ at both mRNA and protein level. The incubation with LX2931, JTE-013 or CAY10444 was able to reduce CA1 damage induced by OGD in organotypic slices and provoked a significant delay of the onset of anoxic depolarization on acute slices. Moreover, S1P₂ and S1P₃ antagonists prevented the increase of TREM2 induced by OGD. Our results reveal a dual role of S1P pathway in brain ischemia: intracellular S1P, degraded via SPL, appears to be beneficial whereas signaling via S1P₂ and S1P₃ is detrimental to the disease. These findings support the notion that SPL, S1P₂ and S1P₃ are promising therapeutic targets in brain ischemia.

2020-09-01·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids2区 · 生物学

Sphingosine 1-phosphate lyase blockade elicits myogenic differentiation of murine myoblasts acting via Spns2/S1P2 receptor axis

2区 · 生物学

Article

作者: Puliti, Elisa ; Bruno, Gennaro ; Donati, Chiara ; Japtok, Lukasz ; Bruni, Paola ; Cencetti, Francesca ; Bernacchioni, Caterina

The bioactive sphingolipid sphingosine 1-phosphate (S1P) has emerged in the last three decades as main regulator of key cellular processes including cell proliferation, survival, migration and differentiation. A crucial role for this sphingolipid has been recognized in skeletal muscle cell biology both in vitro and in vivo. S1P lyase (SPL) is responsible for the irreversible degradation of S1P and together with sphingosine kinases, the S1P producing enzymes, regulates cellular S1P levels. In this study is clearly showed that the blockade of SPL by pharmacological or RNA interference approaches induces myogenic differentiation of C2C12 myoblasts. Moreover, down-regulation of the specific S1P transporter spinster homolog 2 (Spns2) abrogates myogenic differentiation brought about by SPL inhibition or down-regulation, pointing at a role of extracellular S1P in the pro-myogenic action induced by SPL blockade. Furthermore, also S1P₂ receptor down-regulation was found to abrogate the pro-myogenic effect of SPL blockade. These results provide further proof that inside-out S1P signaling is critically implicated in skeletal muscle biology and provide support to the concept that the specific targeting of SPL could represent an exploitable strategy to treat skeletal muscle disorders.

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.

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	-
三阴性乳腺癌	临床前	瑞士	AC BioScience SA	-
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	塞尔维亚	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	捷克	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	药物发现	波兰	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)	襯構顧鹽選廠築窪壓窪(願製積願網蓋鑰鏇選廠) = 齋糧範齋廠膚網壓憲憲衊壓襯壓繭醖襯糧壓醖 (願製憲糧淵醖鏇觸鑰夢, 鏇鑰醖餘壓衊窪築築憲 ~ 廠齋鬱築顧憲醖範鑰窪) 更多	-	2011-12-15
				LX3305 mid dose (Mid Dose)	襯構顧鹽選廠築窪壓窪(願製積願網蓋鑰鏇選廠) = 衊衊遞夢餘遞遞繭憲艱衊壓襯壓繭醖襯糧壓醖 (願製憲糧淵醖鏇觸鑰夢, 廠襯遞艱糧網齋齋鹽願 ~ 壓範壓膚範壓淵糧鬱夢) 更多
NCT00847886 (CTgov)	临床1期	类风湿关节炎	15	LX3305+Methotrexate (LX3305 + Methotrexate)	積窪簾觸憲範膚選艱廠(鹽糧齋糧膚製構構觸鹽) = 積鬱構廠簾遞網窪廠壓築壓淵構鏇鹹選鏇鏇淵 (襯蓋願製廠築餘艱窪鹹, 築廠遞獵鹹繭窪鬱範膚 ~ 繭鑰糧齋範網衊淵網衊) 更多	-	2010-06-03
				Methotrexate (Methotrexate)	積窪簾觸憲範膚選艱廠(鹽糧齋糧膚製構構觸鹽) = 鏇願鑰鹽壓壓顧繭齋鑰築壓淵構鏇鹹選鏇鏇淵 (襯蓋願製廠築餘艱窪鹹, 齋壓糧鑰繭鏇餘襯鏇艱 ~ 範選遞廠壓範築齋襯鹽) 更多
EULAR2009	临床1期	类风湿关节炎 \| 其他疾病	144	LX2931	(襯鹽窪鹹膚醖範繭簾遞) = 糧醖憲繭鏇淵衊積鏇齋範觸簾簾繭鑰蓋餘衊廠 (選顧蓋齋蓋餘製醖鑰鬱 )	-	2009-06-10