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Design, Synthesis, and Biological Evaluation of Sphingosine 1-Phosphate Receptor (S1PR) Agonists

Ferracane, Michael
Format
Thesis/Dissertation; Online
Author
Ferracane, Michael
Advisor
Macdonald, Timothy
Abstract
Sphingosine 1-phosphate (S1P) is produced endogenously in response to a variety of environmental stimuli and serves as a critical signal in the processes of cell proliferation, vascularization, and inflammation. S1P elicits its effects primarily via modulation of its corresponding G protein-coupled receptors: the five sphingosine 1-phosphate receptors (S1PR1-5). This receptor family (especially S1PR1) has proven to be a particularly useful target for the treatment of autoimmune disease; fingolimod (Gilenya, Novartis) is FDA-approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), and it exhibits its activity via modulation of S1PR1,3,4,5. Unfortunately, this broad activity profile also contributes to its deleterious effects, which span from reversible macular edema to potentially lethal bradycardia. The Macdonald and Lynch Labs are interested in developing a second-generation compound that more selectively modulates the S1PRs. Such a compound would be safer and more efficacious than fingolimod for treating those afflicted with RRMS or other autoimmune diseases. We sought to achieve this in two different ways: 1) through synthesis and biological evaluation of a library of rigid analogs of fingolimod and 2) through rational design, synthesis, and biological evaluation of novel compounds. The work described herein outlines present and past attempts to achieve this goal. Based upon previous work, an indane-based fingolimod rigid analog was hypothesized to exhibit more selective agonism of the S1PRs. The indane-based analog was synthesized as a racemic mixture, which demonstrated S1PR1-S1PR5 dual agonist activity in vitro and immunosuppressive activity similar to fingolimod in vivo. Though this rigid analog obtained encouraging preliminary results, it lacks therapeutic potential as a result of limitations in other chemical and biological properties. While the indane-based analog was being evaluated, the 2.8 Å resolution crystal structure of an antagonist-bound S1PR1-T4L chimeric receptor was published. This new knowledge led us to ultimately change our strategy and use computational methods to rationally design new S1PR modulators rather than our previous guess and check method. A computational model of S1PR1 was developed using the Molecular Operating Environment software suite and crystal structure of the antagonist-bound S1PR1-T4L chimeric receptor. Docking studies were then performed using this model and S1PR1 agonists previously reported in the literature; the compounds’ in silico docking study results were compared to their in vitro assay results to create a method that reasonably predicts the activity and binding conformation of the chosen S1PR1 agonists. Using this method, a series of novel compounds were designed and are currently undergoing synthesis. Once finished, the compounds will undergo biochemical evaluation to test the validity and predictability of our model receptor. The validated model will then be used to better understand S1PR function and can be used to develop improved S1PR modulators to treat RRMS.
Language
English
Published
University of Virginia, Department of Chemistry, PHD, 2014
Published Date
2014-06-30
Degree
PHD
Collection
Libra ETD Repository
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