A Potent and Selective S1P1 Antagonist with Efficacy in Experimental Autoimmune Encephalomyelitis

SummaryLymphocyte trafficking is critically regulated by the Sphingosine 1-phosphate receptor-1 (S1P1), a G protein-coupled receptor that has been highlighted as a promising therapeutic target in autoimmunity. Fingolimod (FTY720, Gilenya) is a S1P1 receptor agonist that has recently been approved for the treatment of multiple sclerosis (MS). Here, we report the discovery of NIBR-0213, a potent and selective S1P1 antagonist that induces long-lasting reduction of peripheral blood lymphocyte counts after oral dosing. NIBR-0213 showed comparable therapeutic efficacy to fingolimod in experimental autoimmune encephalomyelitis (EAE), a model of human MS. These data provide convincing evidence that S1P1 antagonists are effective in EAE. In addition, the profile of NIBR-0213 makes it an attractive candidate to further study the consequences of S1P1 receptor antagonism and to differentiate the effects from those of S1P1 agonists

The European Federation for Medicinal Chemistry (EFMC) Best Practice Initiative: Validating Chemical Probes

As part of an initiative aimed to share best practices in Medicinal Chemistry, the European Federation for Medicinal Chemistry (EFMC) is preparing a series of webinars and slide sets focused on the early phase of drug discovery. This educational material is freely accessible through the EFMC. The main target audiences are students or early career scientists and we also believe it will be valuable for experienced practitioners. The first of the series is focused on the generation and validation of high-quality chemical probes, which are critical for drug discovery and more broadly to further our understanding of human biology and disease

The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Phenotypic Drug Discovery

Phenotypic drug discovery has a long track record of delivering innovative drugs and has received renewed attention in the last few years. The promise of this approach, however, comes with several challenges that should be addressed to avoid wasting time and resources on drugs with undesired modes of action or, worse, false-positive hits. In this set of best practices, we go over the essential steps of phenotypic drug discovery and provide guidance on how to increase the chance of success in identifying validated and relevant chemical starting points for optimization: selecting the right assay, selecting the right compound screening library and developing appropriate hit validation assays. Then, we highlight the importance of initiating studies to determine the mode of action of the identified hits early and present the current state of the art