학술논문
Discovery of a Brain-Penetrant S1P3-Sparing Direct Agonist of the S1P1and S1P5Receptors Efficacious at Low Oral Dose.
Document Type
Article
Author
Demont, Emmanuel H.; Arpino, Sandra; Bit, Rino A.; Campbell, Colin A.; Deeks, Nigel; Desai, Sapna; Dowell, Simon J.; Gaskin, Pam; Gray, James R. J.; Harrison, Lee A.; Haynes, Andrea; Heightman, Tom D.; Holmes, Duncan S.; Humphreys, Philip G.; Kumar, Umesh; Morse, Mary A.; Osborne, Greg J.; Panchal, Terry; Philpott, Karen L.; Taylor, Simon
Source
Subject
*IMMUNOSUPPRESSIVE agents
*ORAL medicine
*DRUG dosage
*MULTIPLE sclerosis treatment
*SPHINGOSINE
*G proteins
*CARDIOVASCULAR diseases
*BLOOD-brain barrier
*CENTRAL nervous system
*PHARMACOKINETICS
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Language
ISSN
0022-2623
Abstract
2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1(fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P1, one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P3. Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P1and S1P5in the central nervous system (CNS) may contribute to its efficacy in treating patients with RRMS. We have recently disclosed the structure of an advanced, first generation S1P3-sparing S1P1agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P3-sparing S1P1and S1P5agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (<1 mg p.o. once daily). [ABSTRACT FROM AUTHOR]