The prediction of human response to ONO‐4641, a sphingosine 1‐phosphate receptor modulator, from preclinical data based on pharmacokinetic–pharmacodynamic modeling

Ohno, Tomoya; Hasegawa, Chihiro; Nakade, Susumu; Kitagawa, Junsaku; Honda, Naoki; Ogawa, Michio

doi:10.1002/bdd.719

Cited by 18 publications

(21 citation statements)

References 29 publications

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“…105–107 Developed by Ono Pharmaceutical Co., the compound designated as ceralifimod features close structural similarity with siponimod, also acting specifically on S1P 1 and S1P 5 . 106,107 In an EAE model, ceralifimod caused retention of T and B lymphocytes in lymph nodes, leading to the decrease of lymphocytic infiltration of the CNS, which resulted in the retardation of the disease onset in rats.…”

Section: Structural Diversity Of S1p1 Modulatorsmentioning

confidence: 99%

An update on sphingosine-1-phosphate receptor 1 modulators

Marciniak

Camp

Garcia

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P1) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein–coupled receptor (GPCR) in an attempt to suppress autoimmune disorders. FTY720, also known as fingolimod, is the first oral disease-modifying therapy for MS on the market. In pursuit of improved stability, bioavailability, and efficiency, structural analogues of this initial prodrug have emerged over time. This review covers a brief introduction to the sphingolipid metabolism, the mechanism of action on S1P1, and an updated overview of synthetic sphingosine S1P1 agonists.

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Section: Structural Diversity Of S1p1 Modulatorsmentioning

confidence: 99%

An update on sphingosine-1-phosphate receptor 1 modulators

Marciniak

Camp

Garcia

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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“…Other S1P receptor modulators in clinical development include BAF312 [165], ONO-4641 [166], ponesimod (ACT-128800) [167], and CS-0777 [168]. Few clinical data have yet been published for these investigational drugs.…”

Section: Clinical Effects Of S1p Signalling Altered By Fingolimod In mentioning

confidence: 99%

Fingolimod: Direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy

Groves¹,

Kihara²,

Chun³

2013

Journal of the Neurological Sciences

274

234

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Fingolimod is the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis (MS). Following phosphorylation in vivo, the active agent, fingolimod phosphate (fingolimod-P), acts as a sphingosine 1-phosphate (S1P) receptor modulator, binding with high affinity to four of the five known S1P receptors (S1P1, S1P3, S1P4 and S1P5). The mechanism of action of fingolimod in MS has primarily been considered as immunomodulatory, whereby fingolimod-P modulates S1P1 on lymphocytes, selectively retaining autoreactive lymphocytes in lymph nodes to reduce damaging infiltration into the central nervous system (CNS). However, emerging evidence indicates that fingolimod has direct effects in the CNS in MS. For example, in the MS animal model of experimental autoimmune encephalomyelitis (EAE), fingolimod is highly efficacious in both a prophylactic and therapeutic setting, yet becomes ineffective in animals selectively deficient for S1P1 on astrocytes, despite maintained normal immunologic receptor expression and functions, and S1P-mediated immune activities. Here, we review S1P signalling effects relevant to MS in neural cell types expressing S1P receptors, including astrocytes, oligodendrocytes, neurons, microglia and dendritic cells. The direct effects of fingolimod on these CNS cells observed in preclinical studies are discussed in view of the functional consequences of reducing neurodegenerative processes and promoting myelin preservation and repair. The therapeutic implications of S1P modulation in the CNS are considered in terms of the clinical outcomes of MS, such as reducing MS-related brain atrophy, and other CNS disorders. Additionally, we briefly outline other existing and investigational MS therapies that may also have effects in the CNS.

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“…W-061, a prototype of ONO-4641 [23], has recently been developed to target S1P receptors. In the present study, we evaluated the activity of W-061 on S1P receptors and the effects of this agent on specific T cells, such as Th17 and Treg, in a mouse model of DSS-induced colitis.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Effects of Novel Sphingosine-1-Phosphate Receptor Agonist W-061 in Murine DSS Colitis

et al. 2011

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Although IL-17 is a pro-inflammatory cytokine reportedly involved in various autoimmune inflammatory disorders, its role remains unclear in murine models of colitis. Acute colitis was induced by 2.5% dextran sodium sulfate (DSS) treatment for 5 days. A novel sphingosine-1-phosphate receptor agonist W-061, a prototype of ONO-4641, was orally administered daily, and histopathological analysis was performed on the colon. The number of lymphocytes and their cytokine production were also evaluated in spleen, mesenteric lymph node, Peyer's patch and lamina propria of the colon. Daily administration of W-061 resulted in improvement of DSS-induced colitis, and significantly reduced the number of CD4+ T cells in the colonic lamina propria. Numbers of both Th17 and Th1 cells were reduced by W-061 treatment. W-061, however, had no influence on the number of Treg cells in lamina propria. Thus, Th17 and Th1 cells in lamina propria were thought to be the key subsets in the pathogenesis of DSS-induced colitis. In conclusion, W-061 may be a novel therapeutic strategy to ameliorate acute aggravation of inflammatory bowel diseases.

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The prediction of human response to ONO‐4641, a sphingosine 1‐phosphate receptor modulator, from preclinical data based on pharmacokinetic–pharmacodynamic modeling

Cited by 18 publications

References 29 publications

An update on sphingosine-1-phosphate receptor 1 modulators

An update on sphingosine-1-phosphate receptor 1 modulators

Fingolimod: Direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy

Therapeutic Effects of Novel Sphingosine-1-Phosphate Receptor Agonist W-061 in Murine DSS Colitis

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