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

Abstract

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.

The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1

“…NIBR-14, CYM-5442, ponesimod, or their vehicle (5% DMSO in saline) was given by oral gavage. Ponesimod (ACT-128800, (Z,Z)-5-[3-chloro-4-((2R)-2,3-dihydroxypropoxy)-benzylidene]-2-propylimino-3-o-tolylthiazoli-din-4-one) a selective, reversible, and orally active S1P 1 receptor agonist was prepared by Shanghai ChemPartner Co. according to the method of Bolli et al (28). The final product was purified by preparative HPLC (purity Ͼ97% by LC/MS).…”

“…In contrast, other S1PR 1 agonists potently induce irreversible down-regulation of S1PR 1 resulting in the ubiquitinylation and proteosomal degradation of the receptor, yielding a net decrease in S1PR 1 expression at the plasma membrane (54). S1PR 1 agonists in this class referred to as S1PR 1 modulators include the following: FTY720 (a sphingosine analog that is phosphorylated in vivo by SphK2 to produce its bioactive Sisomeric monophosphate ester FTY720-P, which is an S1P mimetic capable of binding to all S1PRs except S1PR 2 (6)); CYM-5442 (55); and ponesimod (28). These S1PR 1 modulators therefore act as functional antagonists (unlike SEW2871 or S1P) at S1PR 1 to block S1P/S1PR 1 signaling and exert effects similar to those observed with other S1PR 1 antagonists (56).…”

Sphingosine 1-Phosphate (S1P) Receptor Agonists Mediate Pro-fibrotic Responses in Normal Human Lung Fibroblasts via S1P2 and S1P3 Receptors and Smad-independent Signaling

“…We investigated responses that were induced by the nonselective S1PR agonists S1P and FTY720-P (3,13,14), the highly selective S1P 1 R agonist SEW2871 (15), and the selective S1P 1 R agonist ponesimod (16,17), which is currently under clinical investigation for treatment of multiple sclerosis and psoriasis, and we compared them with responses induced by the well described pro-fibrotic mediator TGF-␤1 (18). Here, we show that TGF-␤1 and the two nonselective S1PR agonists, S1P and FTY720-P, were highly pro-fibrotic, whereas ponesimod and SEW2871 were less active or inactive.…”

“…1). These agonists vary in their selectivity towards S1PR subtypes, with S1P and FTY720-P being the least selective (3,13,14), ponesimod displaying improved S1P 1 R selectivity (16,17), and SEW2871 being highly selective for S1P 1 R (15).…”

Biocomparison of THREE formulations of the S1P1 receptor modulator ponesimod in healthy subjects

“…Ponesimod (ACT-128800) is a potent, orally active, selective, reversible S1P 1 receptor modulator [6] currently in clinical development for the treatment of autoimmune diseases and has successfully reached its study end points in recent phase II trials in patients with chronic plaque psoriasis [7] or relapsing-remitting multiple sclerosis [8]. Single-and multiple-dose administration of ponesimod results in a dose-dependent decrease in circulating lymphocytes in healthy subjects and is associated with heart rate reduction, a delay in atrioventricular conduction, and pulmonary effects [9][10][11][12][13].…”