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
- 1 February 2021
- journal article
- research article
- Published by Pharmaceutical Society of Japan in Biological & Pharmaceutical Bulletin
- Vol. 44 (2), 188-196
- https://doi.org/10.1248/bpb.b20-00580
Abstract
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.Keywords
This publication has 17 references indexed in Scilit:
- Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrierJournal of Neuroinflammation, 2012
- Type 1 Diabetes: Etiology, Immunology, and Therapeutic StrategiesPhysiological Reviews, 2011
- Prevention of Diabetes by FTY720-Mediated Stabilization of Peri-Islet Tertiary Lymphoid OrgansDiabetes, 2010
- A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple SclerosisThe New England Journal of Medicine, 2010
- Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple SclerosisThe New England Journal of Medicine, 2010
- Promotion of Lymphocyte Egress into Blood and Lymph by Distinct Sources of Sphingosine-1-PhosphateScience, 2007
- Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transitThe Journal of Experimental Medicine, 2005
- Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart RateOnline Journal of Public Health Informatics, 2004
- Immune Cell Regulation and Cardiovascular Effects of Sphingosine 1-Phosphate Receptor Agonists in Rodents Are Mediated via Distinct Receptor SubtypesThe Journal of pharmacology and experimental therapeutics, 2004
- The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate ReceptorsJournal of Biological Chemistry, 2002