Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) that is characterized by inflammation leading to astrogliosis, demyelination, and loss of oligodendrocytes and neurons. Recently, the first oral disease-modifying therapy Fingolimod/FTY720 (Gilenya�) was approved in patients with relapsing forms of MS. In addition to direct effects on neural cells, this first-in-class sphingosine 1-phosphate (S1P) receptor modulator reduces CNS damage by interfering with lymphocyte recruitment which is critically regulated by the Sphingosine-1-phosphate receptor-1 (S1P1). This G-protein coupled receptor has been identified as promising therapeutic target in autoimmune diseases, after recognizing that S1P receptor agonists down-regulate the S1P1 receptor on T-cells and prevent lymphocyte egress from lymphoid organs. This �functional antagonism� provided a strong rationale for S1P1 receptor blockade in autoimmune diseases. Herein we present the identification of a novel S1P1 receptor antagonist scaffold by HTS, followed by a successful optimization to afford single digit nanomolar tool compounds for subcutaneous administration. First in vivo studies in rats confirmed the immunomodulatory properties, kicking-off a broad strategy to address the scaffold inherent bioavailability issues. These efforts ultimately led via a prodrug approach to the discovery of NIBR-0213. Oral administration of this highly potent and selective S1P1 receptor antagonist induces long lasting reduction of peripheral blood lymphocyte counts leading to efficacy in relevant animal models of autoimmune diseases.

Discovery of highly potent S1P<sub>1</sub> receptor antagonists with in vivo efficacy

245th National Meeting (2013)

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Discovery of highly potent S1P1 receptor antagonists with in vivo efficacy

Discovery of highly potent S1P₁ receptor antagonists with in vivo efficacy