Delving into the Latest Updates on Ceralifimod with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

S1PR1 x S1PR5

Action

agonists

Mechanism

S1PR1 agonists(Sphingosine 1-phosphate receptor Edg-1 agonists), S1PR5 agonists(Sphingosine 1-phosphate receptor Edg-8 agonists)

Therapeutic Areas

Immune System DiseasesNervous System DiseasesOther Diseases

Active Indication-

Inactive Indication

Multiple Sclerosis, Relapsing-Remitting

Originator Organization

Ono Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Merck KGaA

Ono Pharmaceutical Co., Ltd.

License Organization

Ono Pharmaceutical Co., Ltd.Merck Serono SA

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC27H33NO4

InChIKeyQDDQIPUKAXBMBX-UHFFFAOYSA-N

CAS Registry891859-12-4

ONO-4641 is a second-generation sphingosine 1-phosphate (S1P) receptor modulator that exhibits selectivity for S1P receptors 1 and 5. Treatment with ONO-4641 leads to a reduction in magnetic resonance imaging disease measures in patients with relapsing-remitting multiple sclerosis. The objective of this study was to explore the potential impact of ONO-4641 treatment based on its immunomodulatory effects. Severe aplastic anemia is a bone marrow (BM) failure disease typically caused by aberrant immune destruction of blood progenitors. Although the T helper type 1-mediated pathology is well described for aplastic anemia, the molecular mechanisms driving disease progression remain undefined. We evaluated the efficacy of ONO-4641 in a mouse model of aplastic anemia. ONO-4641 reduced the severity of BM failure in a dose-dependent manner, resulting in higher blood and BM cell counts. By evaluating the mode of action, we found that ONO-4641 inhibited the infiltration of donor-derived T lymphocytes to the BM. ONO-4641 also induced the accumulation of hematopoietic stem cells in the BM of model mice. These observations indicate, for the first time, that S1P receptor modulators demonstrate efficacy in the mouse model of aplastic anemia and suggest that treatment with ONO-4641 might delay the progression of aplastic anemia. SIGNIFICANCE STATEMENT: ONO-4641 is a second-generation sphingosine 1-phosphate (S1P) receptor modulator selective for S1P receptors 1 and 5. In this study, we demonstrated that ONO-4641 regulates the trafficking of T lymphocytes along with hematopoietic stem and progenitor cells, leading to alleviation of pancytopenia and destruction of bone marrow in a bone marrow failure-induced mouse model mimicking human aplastic anemia.

01 Feb 2021·Biological and Pharmaceutical BulletinQ4 · MEDICINE

Preventive and Therapeutic Efficacy of ONO-4641, a Selective Agonist for Sphingosine 1-Phosphate Receptor 1 and 5, in Preclinical Models of Type 1 Diabetes Mellitus

Q4 · MEDICINE

Article

Author: Shioya, Hiroki ; Kurata, Haruto ; Hiraizumi, Kenji ; Habashita, Hiromu ; Sato, Kazutoyo ; Inagaki, Yuichi ; Hoshino, Tomohiro ; Nakade, Shinji

ONO-4641, 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid (ceralifimod), is a second-generation sphingosine 1-phosphate receptor agonist selective for sphingosine 1-phosphate receptors 1 and 5, and has clinical effects in multiple sclerosis. The objective of the present study was to explore other potential indications for ONO-4641 based on its immunomodulatory effects. ONO-4641 was tested in non-obese diabetic (NOD) mice, an animal model of spontaneous type 1 diabetes mellitus, an autoimmune disease with unmet medical needs. ONO-4641 at a dose of 0.1 mg/kg prevented the onset of diabetes mellitus in NOD mice. Furthermore, ONO-4641 at doses of 0.03 and 0.1 mg/kg decreased diabetic prevalence in NOD mice after the onset of diabetes mellitus in a dose-dependent manner. Histopathological analysis demonstrated that insulin-positive areas in the islets of mice administered 0.03 and 0.1 mg/kg ONO-4641 showed a tendency of high values although they were not significantly different from the Control group, which was treated with vehicle. These observations suggest ONO-4641 may delay the onset and progression of type 1 diabetes mellitus.

08 Nov 2018·Journal of Medicinal ChemistryQ1 · MEDICINE

Where Do Recent Small Molecule Clinical Development Candidates Come From?

Q1 · MEDICINE

Review

Author: Brown, Dean G. ; Boström, Jonas

An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.

100 Deals associated with Ceralifimod

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16123

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis, Relapsing-Remitting	Phase 2	Belgium	Ono Pharmaceutical Co., Ltd.	01 Oct 2010
Multiple Sclerosis, Relapsing-Remitting	Phase 2	Russia	Merck KGaA	01 Oct 2010
Multiple Sclerosis, Relapsing-Remitting	Phase 2	Germany	Ono Pharmaceutical Co., Ltd.	01 Oct 2010
Multiple Sclerosis, Relapsing-Remitting	Phase 2	Ukraine	Ono Pharmaceutical Co., Ltd.	01 Oct 2010
Multiple Sclerosis, Relapsing-Remitting	Phase 2	Japan	Ono Pharmaceutical Co., Ltd.	01 Oct 2010
Multiple Sclerosis, Relapsing-Remitting	Phase 2	United States	Merck KGaA	01 Oct 2010
Multiple Sclerosis, Relapsing-Remitting	Phase 2	Canada	Ono Pharmaceutical Co., Ltd.	01 Oct 2010
Multiple Sclerosis, Relapsing-Remitting	Phase 2	Greece	Merck KGaA	01 Oct 2010
Multiple Sclerosis, Relapsing-Remitting	Phase 2	Czechia	Ono Pharmaceutical Co., Ltd.	01 Oct 2010
Multiple Sclerosis, Relapsing-Remitting	Phase 2	Poland	Ono Pharmaceutical Co., Ltd.	01 Oct 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01226745 (DreaMS, CTgov)	Phase 2	Multiple Sclerosis, Relapsing-Remitting	340	ONO-4641 (ONO-4641 0.10 mg - 0.10 mg)	puewnjipuk(badioqpddu) = njombvrayp yzowxlpocq (ounuqnkdqt, pigktpctth - fyudvocpyn) View more	-	12 Jul 2016
				ONO-4641 (ONO-4641 0.05 mg - 0.05 mg)	puewnjipuk(badioqpddu) = ekakjsxbci yzowxlpocq (ounuqnkdqt, defsgxflkp - nexlhflfli) View more
DreaMS study (ECTRIMS2013)	Not Applicable	Multiple Sclerosis	360	Placebo/0.05 mg ONO-4641	ffcdiuwhxi(qwiqqmfwgl) = brmxcdnpzb mevfyawkyg (amruhiyuwy )	-	30 Sep 2013
				Placebo/0.10 mg ONO-4641	ffcdiuwhxi(qwiqqmfwgl) = akbeotjytt mevfyawkyg (amruhiyuwy )
DreaMS study (ECTRIMS2013)	Not Applicable	Multiple Sclerosis	343	ONO-4641 0.10mg	(nsocfrospm): ARR = 0.16 (95% CI, 0.08 - 0.33), P-Value = 0.005	-	30 Sep 2013
				Placebo/ONO-4641 0.05mg
NCT01081782 (DreaMS, AAN2013)	Phase 2	Multiple Sclerosis, Relapsing-Remitting	-	Placebo	(nsufwymrof) = nbqcqeveqf xnrplkohqn (yearxdrxcc ) View more	Positive	12 Feb 2013
				ONO-4641 0.05 mg	(nsufwymrof) = xkpedspasf xnrplkohqn (yearxdrxcc ) View more
NCT01081782 \| NCT01226745 (DreaMS, AAN2013)	Phase 2	Multiple Sclerosis, Relapsing-Remitting	-	Placebo	lqoibbxgza(derotrztom): relative reduction = 70 (95% CI, 54 - 81)	-	12 Feb 2013
				ONO-4641 0.05 mg