Improving Potency and Oral Bioavailability of Spinster Homolog 2 (Spns2) Inhibitor: A Structure-Activity Relationship Study

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dc.contributor.authorDunnavant, Kyle Jacoben
dc.contributor.committeechairSantos, Websteren
dc.contributor.committeememberMevers, Emily Elizabethen
dc.contributor.committeememberTanko, James M.en
dc.contributor.committeememberLowell, Andrew Nesemannen
dc.contributor.departmentChemistryen
dc.date.accessioned2024-06-14T08:00:30Zen
dc.date.available2024-06-14T08:00:30Zen
dc.date.issued2024-06-13en
dc.description.abstractgeneralIn healthy individuals, the autoimmune system is the body's natural defense against foreign materials and organisms. The main tools utilized for this defense mechanism are immune cells. However, in patients suffering from autoimmune diseases, the autoimmune system is overactive resulting in its attack on healthy cells, which leads to reduced or eliminated function of the targeted organs. To suppress these overreactive immune responses, pharmaceutical intervention is needed. An integral part of autoimmune response is the lipid sphingosine-1-phosphate (S1P). Interactions of S1P with its response-inducing receptors prompts the release of immune cells, lymphocytes in particular, from lymph tissue to migrate and participate in the invoked immune response. The pharmaceutical industry has produced five FDA approved drugs that disrupt this S1P-receptor interaction by blocking the receptor to reduce the autoimmune response in patients suffering from autoimmune diseases such as multiple sclerosis and ulcerative colitis. However, these treatments had adverse side effects on the cardiovascular system due to the presence of S1P receptors in the heart. Due to this, there is attraction to target a different node of the S1P signaling pathway to avoid these side effects while still suppressing the immune response. A node that is a viable target for therapeutic target that has recently become the focus of medicinal chemistry campaigns is the transporter protein spinster homolog 2 (Spns2). This protein is responsible for the transport of S1P from intracellular space to extracellular space to interact with its receptors and induce the immune response. Recently, our group has developed several effective inhibitors of Spns2. In this dissertation, several improvements of previously reported inhibitors are revealed. The pinnacle of this work is the development of 4.22v that is optimized to have drug-like properties for testing in mice. Administration of 4.22v to mice resulted in reduced circulating lymphocytes and without showing signs of toxicity following chronic dosing for 14 days. These results suggest that 4.22v is a potential drug candidate and is currently undergoing further biological evaluation.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:40143en
dc.identifier.urihttps://hdl.handle.net/10919/119439en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectSphingosine-1-phosphateen
dc.subjectS1Pen
dc.subjectSpns2en
dc.subjecttransporter inhibitoren
dc.subjectlymphopeniaen
dc.subjectautoimmune diseaseen
dc.subjectmultiple sclerosisen
dc.subjectulcerative colitisen
dc.subjectrenal fibrosisen
dc.subjectstructure-activity relationship studyen
dc.titleImproving Potency and Oral Bioavailability of Spinster Homolog 2 (Spns2) Inhibitor: A Structure-Activity Relationship Studyen
dc.typeDissertationen
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

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