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Sphingosine 1-phosphate receptor modulators for the treatment of inflammatory bowel disease and other immune-mediated diseases

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Abstract

Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease involving the ileum, rectum, and colon. Clinical manifestations include diarrhea, abdominal pain, and bloody stool. The disease includes ulcerative colitis (UC) and Crohn’s disease (CD). Biological therapies, including anti-TNF, anti-IL-12/23, and anti-integrins, improved the treatment of IBD, but they lack universal effectiveness and uniform immunogenicity. The advantage of small molecules over biological therapies includes tolerance of low immunogenicity, oral administration, and low manufacturing cost. Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a signaling molecule that is involved in immunological, cardiovascular, and neurological processes through interaction with sphingosine 1-phosphate receptors (S1PRs). S1P binds to S1PRs on the cell surface, activating multiple downstream signaling pathways such as AKT, Rac, Rho, ERK and PKC, causing a wide range of biological effects. S1PR is a G protein-coupled receptor with five subtypes: S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. S1PR1 to 3 are expressed in various tissues, and S1PR4 is expressed in lymph nodes. S1PR5 is expressed in brain and skin. The S1PR agonists arise as new strategies for regulating downstream cytokine signaling in immune-mediated diseases. This article reviews the mechanisms of immune regulation by S1P/S1PRs, the pharmacokinetics of S1PR modulators (Fingolimod, Ozanimod, Etrasimod, Siponimod, among others), and the related clinical data.

S1PR subtypes and the medications that functionally modulate them

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Abbreviations

S1PR:

Sphingosine-1-phosphate receptor

EDG:

Endothelial differentiation gene

Akt:

Serine/threonine kinase (protein kinase B)

Rac:

Protein kinase B

ERK:

Extracellular regulated protein kinases

PLC:

Phospholipase C

PKC:

Protein kinase C

Rho:

Ras homolog gene family

ROCK/ROK:

Rho activates Rho kinase

CNS:

Central nervous system

FDA:

Food and Drug Administration

UC:

Ulcerative colitis

CD:

Crohn’s disease

IBD:

Inflammatory bowel disease

CDAI:

Crohn’s disease activity index

MS:

Multiple sclerosis

JAK:

Janus kinase

STAT:

Signal transducer and activator of transcription

BBB:

Blood brain barrier

BMS:

Bristol-Myers Squibb

ARR:

Annual relapse rate

OASIS:

Oxford Acute Severity of Illness Score

mMCS:

Modified Mayo Clinic score

MCS:

Mayo Clinic score

BOLD:

Blood oxygen level dependent

RRMS:

Relapsing-remitting multiple sclerosis

SPMS:

Secondary progressive multiple sclerosis

SLE:

Systemic lupus erythematosus

AE:

Adverse effect

TEAES:

Treatment-emergent AEs

NF-κB:

Nuclear factor kappa-B

IL:

Interleukin

COX-2:

Cyclooxygenase-2

RA:

Rheumatoid arthritis

OR:

Odds ratio

CI:

Confidence interval

Tmax:

Peak time

Cmax:

Peak concentration

AV block:

Atrioventricular block

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Authors and Affiliations

  1. School of Pharmacy, Nanjing Tech University, Nanjing, 210031, PR China

    Lifan Xu & Yubin Wang

  2. Nanjing Eternal Institute of Pharmaceutical Research, Nanjing, 211500, PR China

    Peng Lu

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Idea for the article: YW; Performed the literature search and data analysis: LX; Drafted the work: LX; Critically revised the work: PL.

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Xu, L., Lu, P. & Wang, Y. Sphingosine 1-phosphate receptor modulators for the treatment of inflammatory bowel disease and other immune-mediated diseases. Med Chem Res 31, 2074–2088 (2022). https://doi.org/10.1007/s00044-022-02961-4

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