2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1 Receptor Agonists

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• 作者：Martin H. Bolli ; Stefan Abele ; Christoph Binkert ; Roberto Bravo ; Stephan Buchmann ; Daniel Bur ; John Gatfield ; Patrick Hess ; Christopher Kohl ; Cline Mangold ; Boris Mathys ; Katalin Menyhart ; Claus Mller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 27, 2010
• 年：2010
• 卷：53
• 期：10
• 页码：4198-4211
• 全文大小：1002K
• 年卷期：v.53,no.10(May 27, 2010)
• ISSN：1520-4804

文摘

Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays a wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P₁ through S1P₅. Agonists of the S1P₁ receptor block the egress of T-lymphocytes from thymus and lymphoid organs and hold promise for the oral treatment of autoimmune disorders. Here, we report on the discovery and detailed structure−activity relationships of a novel class of S1P₁ receptor agonists based on the 2-imino-thiazolidin-4-one scaffold. Compound 8bo (ACT-128800) emerged from this series and is a potent, selective, and orally active S1P₁ receptor agonist selected for clinical development. In the rat, maximal reduction of circulating lymphocytes was reached at a dose of 3 mg/kg. The duration of lymphocyte sequestration was dose dependent. At a dose of 100 mg/kg, the effect on lymphocyte counts was fully reversible within less than 36 h. Pharmacokinetic investigation of 8bo in beagle dogs suggests that the compound is suitable for once daily dosing in humans.