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/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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9

项与 LX-2931 相关的文献（医药）

2025-03-01·Behavioural Brain Research

Exploring the contribution of the dopaminergic and noradrenergic systems in the antidepressant-like action of 1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethanone in mice

Article

作者: Alves, Diego ; Goulart, Taís Barcelos ; Ledebuhr, Kauane Nayara Bahr ; Zuge, Narryman Pinto ; Presa, Marcelo Heinemann ; da Rocha, Marcia Juciele ; Bortolatto, Cristiani Folharini ; Brüning, César Augusto

1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethanone (ETAP) is a novel hybrid compound containing 1,2,3-triazole and acetophenone. It exhibits antidepressant-like effects in male mice, linked to modulation of serotonergic receptors and monoamine oxidase A (MAO-A) inhibition. This study aimed to evaluate the involvement of the dopaminergic and noradrenergic systems, as well as MAO-B activity inhibition, in the antidepressant-like effect of ETAP in male mice, and to evaluate the antidepressant-like effect of ETAP in female mice. Male mice were treated with different dopaminergic and noradrenergic receptors antagonists 15 min before administering ETAP (1 mg/kg, intragastrically, i.g.). The tail suspension test (TST) was performed 30 minutes later. Different male mice were treated with ETAP (1 mg/kg, i.g.), and 30 minutes later, were euthanized to assess MAO-B activity in the prefrontal cortex and hippocampus. To evaluate the antidepressant-like of ETAP in female mice, ETAP (1 mg/kg, i.g.) was administered, followed by the TST and the forced swimming test (FST) 30 minutes later. The dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally, i.p.), SCH23390 (0.01 mg/kg, subcutaneously, s.c.), and sulpiride (50 mg/kg, i.p.), as well the noradrenergic antagonists prazosin (1 mg/kg, i.p.), yohimbine (1 mg/kg, i.p.), and propranolol (2 mg/kg, i.p.), prevented the antidepressant-like effect of ETAP in the TST. MAO-B activity was unaffected by ETAP in both the prefrontal cortex and hippocampus. ETAP (1 mg/kg, i.g.) induced a significant antidepressant-like effect in female mice in the TST and FST. These findings provide valuable insights into the antidepressant-like effect of ETAP, highlighting its potential for developing more effective depression treatments.

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.

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
达里耶病	临床2期	法国	Dermecular Therapeutics, Inc.	2018-05-24
类风湿关节炎	临床2期	捷克	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	临床2期	波兰	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	临床2期	美国	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	临床2期	塞尔维亚	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	临床2期	匈牙利	Lexicon Pharmaceuticals, Inc.	2009-07-01
类风湿关节炎	临床2期	保加利亚	Lexicon Pharmaceuticals, Inc.	2009-07-01
胰腺癌	临床2期	-	AC BioScience SA初创企业	-
结直肠癌	临床前	瑞士	AC BioScience SA初创企业	-
三阴性乳腺癌	临床前	瑞士	AC BioScience SA初创企业	-

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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)	範繭艱鹹齋鬱齋簾憲製(觸醖觸鹹醖鏇鏇艱艱遞) = 願鹽廠觸觸網醖願築鑰觸鑰夢壓簾壓觸襯淵淵 (壓鏇壓淵鏇網鏇糧顧襯, 築繭鹹餘廠窪鬱蓋獵廠 ~ 夢顧艱範網蓋廠糧蓋築) 更多	-	2011-12-15
				LX3305 mid dose (Mid Dose)	範繭艱鹹齋鬱齋簾憲製(觸醖觸鹹醖鏇鏇艱艱遞) = 範鑰窪廠構夢鏇鏇獵夢觸鑰夢壓簾壓觸襯淵淵 (壓鏇壓淵鏇網鏇糧顧襯, 糧鏇衊憲範齋鏇襯積範 ~ 衊醖廠鑰願構餘顧獵衊) 更多
NCT00847886 (CTgov)	临床1期	类风湿关节炎	15	LX3305+Methotrexate (LX3305 + Methotrexate)	鹽膚糧願糧範簾製製願(憲憲壓網鑰鬱築簾觸膚) = 糧廠積鹹製繭鹹衊淵淵積鏇廠獵積壓窪繭鏇鹹 (壓醖壓顧鑰淵遞遞遞蓋, 遞齋鹽膚醖顧壓壓廠繭 ~ 網鬱壓觸觸觸繭築觸願) 更多	-	2010-06-03
				Methotrexate (Methotrexate)	鹽膚糧願糧範簾製製願(憲憲壓網鑰鬱築簾觸膚) = 觸網蓋網簾範醖壓繭範積鏇廠獵積壓窪繭鏇鹹 (壓醖壓顧鑰淵遞遞遞蓋, 憲鬱獵顧餘廠鑰壓餘觸 ~ 鏇醖網鏇願簾淵廠鑰壓) 更多
EULAR2009	临床1期	类风湿关节炎 \| 其他疾病	144	LX2931	(獵顧築獵繭簾襯夢襯築) = 衊鏇衊艱簾鹽壓願襯觸憲蓋顧鹹糧衊齋夢壓廠 (醖構選積製壓築構觸簾 )	-	2009-06-10