2 research outputs found

    Potent and Selective Agonists of Sphingosine 1‑Phosphate 1 (S1P<sub>1</sub>): Discovery and SAR of a Novel Isoxazole Based Series

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    Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P<sub>1–5</sub>) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P<sub>1</sub>, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P<sub>1</sub>. Isoxazole <b>6d</b> demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis

    Identification of Tricyclic Agonists of Sphingosine-1-phosphate Receptor 1 (S1P<sub>1</sub>) Employing Ligand-Based Drug Design

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    Fingolimod (<b>1</b>) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P<sub>1</sub> is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P<sub>1</sub> while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P<sub>1</sub> with selectivity over S1P<sub>3</sub> and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound <b>10</b> had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model
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