Discovery of a Brain-Penetrant S1P3-Sparing Direct Agonist of the S1P1 and S1P5 Receptors Efficacious at Low Oral Dose

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• 作者：Emmanuel H. Demont ; Sandra Arpino ; Rino A. Bit ; Colin A. Campbell ; Nigel Deeks ; Sapna Desai ; Simon J. Dowell ; Pam Gaskin ; James R. J. Gray ; Lee A. Harrison ; Andrea Haynes ; Tom D. Heightman ; Duncan S. Holmes ; Philip G. Humphreys ; Umesh Kumar ; Mary A. Morse ; Greg J. Osborne ; Terry Panchal ; Karen L. Philpott ; Simon Taylor ; Robert Watson ; Robert Willis ; Jason Witherington
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6724-6733
• 全文大小：1047K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

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 S1P₁ and S1P₅ in 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 S1P₁ agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P₃-sparing S1P₁ and S1P₅ agonists 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).