Recent progress in the development of selective S1P1 receptor agonists for the treatment of inflammatory and autoimmune disorders

Abstract

Background : The sphingosine-1-phosphate receptor 1 (S1P1) belongs to the endothelial differentiation gene family of G-protein-coupled receptors involved in embryonic development, cellular differentiation and survival, adherence and tight junction assembly, and leukocyte trafficking. In vivo S1P1 is required for egress of thymocytes into the blood and of naive lymphocytes from secondary lymphoid organs back into the lymph. Downregulation of S1P1 disrupts lymphocyte migration, tissue homing and recirculation. To explore the immunomodulatory potential of S1P1, pharma is developing S1P1-selective agonists for treating autoimmune and inflammatory disorders. FTY720 (fingolimod, Novartis AG), a nonselective S1P1 agonist that induces sustained lymphopenia, is a promising pseudolipid aminodiol prodrug that has been shown in preclinical and early clinical trials to be effective in suppressing various autoimmune conditions and to aid in acute organ transplant, and is currently in pivotal Phase III clinical trials for relapsing-remitting multiple sclerosis. Objective : In this review article, we outline recent advances made in the discovery and patenting of new small-molecule S1P1 selective agonists and summarize a rapidly growing body of intellectual property. Conclusion : Fingolimod-like S1P1 agonists with a novel mechanism of action have emerged as promising immunosuppressants. S1P1 agonists induce T-cell sequestration in lymph nodes and Peyer's patches, diminishing their ability to reach distant sites and cause pathology. Preclinical studies have already provided preliminary evidence that low-dose treatment with fingolimod in conjunction with subtherapeutic doses of ciclosporin A and tacrolimus enable potent immunosuppression in the absence of immediately serious side effects. Future efforts will determine whether S1P1 agonists do indeed synergize with existing DMAs to create new mutidrug paradigms with superior efficacy and safety for the treatment of autoimmune diseases and the prevention of organ transplant rejection.

An update on sphingosine-1-phosphate receptor 1 modulators

“…63,64 The much more potent ( R ) enantiomer acts as an immunosuppressant by inhibiting virus–induced chemokine and cytokine production. 64,65 …”

“…Thus, it does not require bioactivation by phosphorylation, and yet is highly specific for S1P 1 , with a >100–fold selectivity relative to S1P 2–5 . 65,89,91 The carbamoylnicotinamide synthesized by Pennington et al causes substantial depletion of lymphocyte circulation (78–81% depletion in rats) 24 hrs after a single oral dose of 1 mg/kg, and has an EC 50 value of 35 nM with 96% efficacy. 89 Respective quinolinone derivatives were reported to inhibit lymphocyte recirculation and egress with equivalent S1P 1 selectivity.…”

Regulation of Mammalian Physiology, Development, and Disease by the Sphingosine 1-Phosphate and Lysophosphatidic Acid Receptors

“…Numerous emerging reports indicate roles in mammalian biology for other, less well-characterized LP members, as well 8 . In the past decade, our understanding of LP biology has expanded exponentially, fueled by the identification of LP receptors, generation and analysis of LPA and S1P-receptor knockout mice, and small molecule compounds functioning as receptor-specific agonists or antagonists 3,9,10 .…”

Integrating the puzzle pieces: The current atomistic picture of phospholipid–G protein coupled receptor interactions

“…Later discovery that the long-lasting removal of S1P 1 from the cell surface occurs after stimulation by FTY720-phosphate (functional antagonism [4]) and is responsible for lymphocyte trafficking effects [5] stimulated consideration of antagonists, as well as agonists. Non-lipid molecules with S1P receptor activity appeared first in the patent literature (reviewed in [6]) and subsequently in peer-reviewed journals. These non-lipid molecules have not often been linked with specific binding sites through mutagenesis studies or confirmation of strictly competitive binding modes.…”