2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1Receptor Agonists

作者：Martin H. Bolli, Stefan Abele, Christoph A. Binkert, Roberto Bravo, Stephan Buchmann, Daniel Bur, John Gatfield, Patrick Hess, Christopher Kohl, Céline Mangold, Boris Mathys, Katalin Menyhart, Claus Müller, Oliver Nayler, Michael W. Scherz, Gunther Schmidt, Virginie Sippel, Beat Steiner, Daniel S. Strasser, Alexander Treiber, Thomas Weller · 发表于：Journal of Medicinal Chemistry · 年份：2010 · DOI：10.1021/jm100181s · 被引用次数：179 · 研究领域：Sphingolipid Metabolism and Signaling、Erythrocyte Function and Pathophysiology、Inflammasome and immune disorders

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 S1P(1) through S1P(5). Agonists of the S1P(1) 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 S1P(1) 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 S1P(1) 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.