Delving into the Latest Updates on LX-2931 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

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

+ [4]

Target

SGPL1

Mechanism

SGPL1 inhibitors(Sphingosine-1-phosphate lyase 1 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [1]

Active Indication

Pancreatic CancerColorectal CancerTriple Negative Breast Cancer

Inactive Indication

Darier DiseaseMuscular Dystrophy, DuchenneRheumatoid Arthritis

Originator Organization

Lexicon Pharmaceuticals, Inc.

Active Organization

AC BioScience SAStartup

Inactive Organization

Lexicon Pharmaceuticals, Inc.Dermecular Therapeutics, Inc.

Drug Highest PhasePhase 2

First Approval Date-

RegulationOrphan Drug (EU)

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Structure

Molecular FormulaC9H15N3O5

InChIKeyAMXVYJYMZLDINS-RSWLNLDNSA-N

CAS Registry948840-25-3

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.

01 Aug 2019·BoneQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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.

01 Nov 2016·American Journal of Physiology-Lung Cellular and Molecular PhysiologyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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 Deals associated with LX-2931

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06297

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Muscular Dystrophy, Duchenne	Phase 2	US	Lexicon Pharmaceuticals, Inc.	-
Pancreatic Cancer	Phase 2	-	AC BioScience SAStartup	-
Rheumatoid Arthritis	Preclinical	CZ	Lexicon Pharmaceuticals, Inc.	01 Jul 2009
Colorectal Cancer	Preclinical	CH	AC BioScience SAStartup	-
Darier Disease	Discovery	FR	Dermecular Therapeutics, Inc.	24 May 2018
Rheumatoid Arthritis	Discovery	PL	Lexicon Pharmaceuticals, Inc.	01 Jul 2009
Rheumatoid Arthritis	Discovery	US	Lexicon Pharmaceuticals, Inc.	01 Jul 2009
Rheumatoid Arthritis	Discovery	HU	Lexicon Pharmaceuticals, Inc.	01 Jul 2009
Rheumatoid Arthritis	Discovery	BG	Lexicon Pharmaceuticals, Inc.	01 Jul 2009
Rheumatoid Arthritis	Discovery	RS	Lexicon Pharmaceuticals, Inc.	01 Jul 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00903383 (CTgov)	Phase 2	Rheumatoid Arthritis	208	LX3305 low dose (Low Dose)	kovwhyplbv(tdrruapmac) = ppmwootetm kuxmysoody (zpqdevbcnt, hypdtcnhol - wzojocvpng) View more	-	15 Dec 2011
				LX3305 mid dose (Mid Dose)	kovwhyplbv(tdrruapmac) = uyuudbfrfs kuxmysoody (zpqdevbcnt, jnsxhglzzx - sgdkgludkz) View more
NCT00847886 (CTgov)	Phase 1	Rheumatoid Arthritis	15	LX3305+Methotrexate (LX3305 + Methotrexate)	gkwtswawra(nzvifipboe) = hcecwbsxwm numnhltryv (qolbcjuopc, krazwzensr - bptagptvgc) View more	-	03 Jun 2010
				Methotrexate (Methotrexate)	gkwtswawra(nzvifipboe) = hrppcbojsf numnhltryv (qolbcjuopc, qhdubsayye - fixyrfslie) View more
EULAR2009	Phase 1	Rheumatoid Arthritis \| Other Diseases	144	LX2931	(bwiinalvjv) = jqntfoitoq xmgikheqhr (giwdhgpjml )	-	10 Jun 2009