2-Imino-thiazolidin-4-one Derivatives as Potent, Orally Active S1P1Receptor Agonists
| Autor: | Patrick Hess, Gunther Schmidt, Katalin Menyhart, Daniel S. Strasser, Alexander Treiber, Claus Müller, Beat Steiner, Daniel Bur, Christopher Kohl, Roberto Bravo, Christoph Binkert, John Gatfield, Stephan Buchmann, Michael Scherz, Boris Mathys, Virginie Sippel, Stefan Abele, Martin Bolli, Oliver Nayler, Thomas Weller, Céline Mangold |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Agonist medicine.drug_class Lymphocyte Administration Oral Pharmacology Cell Line Radioligand Assay Structure-Activity Relationship Cricetulus Dogs Pharmacokinetics Cricetinae Drug Discovery Extracellular medicine Animals Humans Structure–activity relationship Lymphocyte Count Rats Wistar Receptor Chemistry Stereoisomerism High-Throughput Screening Assays Rats Receptors Lysosphingolipid Thiazoles medicine.anatomical_structure Ponesimod Cell culture Hepatocytes Microsomes Liver Thiazolidines Molecular Medicine lipids (amino acids peptides and proteins) Imines medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 53:4198-4211 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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