Part I: Design, Synthesis, and Biological Activity of NMDA Receptor Antagonists Part II: Design and Synthesis of Measles Virus Inhibitors Open Access

Murray, Ernest (2010)

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Part I of this thesis elaborates on the design and synthesis of new N-methyl D-aspartate (NMDA) receptor antagonists in the effort to treat stroke. The NMDA receptor is a glutamate receptor that has been found to be sensitive to pH fluctuations in the extracellular space. During a stroke, ischemia causes elevated proton concentration allowing the opportunity to tune receptor antagonist design towards neuroprotection in vulnerable conditions. Phenylethanolamines (like ifenprodil) are known NMDA subunit NR2B antagonists that allosterically affect the gate opening at different pHs. Our chiral 1-(phenethylamino)-3-phenoxypropan-2-ol scaffold compounds (also known as "93 series") act similarly and have been found to utilize the proton sensor of the NMDA receptor to provide up to a 17 fold inhibition at pH 6.9 compared to the physiological pH of 7.3. Our newest scaffold the 96 series is similar to the 93 series but lacks chirality, and has also exhibited potent IC50 values at pH 6.9.

Part II discusses new efforts in resisting measles virus proliferation through the use of novel small molecules. The measles virus (of the paramyxovirus family) is a serious concern in third world countries where vaccination systems are not at the 95% coverage rate required to stop the spread. No effective retroviral treatments have been developed for victims of this disease. Fusion (MV-F) protein, a protein associated with viral entry into the host cell, may be an effective path to treatment. Data from the mutagenesis of MV-F along with computational homology models have indicated the possible location of an allosteric inhibitor binding site. Three new compounds were synthesized with pyridinyl moeties designed to increase potency. Another likely target for the measles virus life cycle is the RNA-dependent RNA polymerase (RDRP). Though the mechanism action is not known, we have development several very potent RDRP inhibitors based on a lead compound discovered in a screening library. Our most potent inhibitors come from targeting the RDRP, and these molecules can inhibit measles virus viability in the nanomolar concentrations.

Table of Contents

1. Design, Synthesis, and Biological activity of NMDA Receptor Antagonists...1 1.1. Statement of Purpose...1 1.2 Background and Introduction...3 1.2.1 Neurological Disorders and the NMDA Receptor...3 1.2.2 Development of NR2B Selective NMDA Receptor Antagonists...5 1.3 Results and Discussions...8 1.3.1 Replacement of Chiral Hydroxyl Group with Fluorine...8 1.3.2 Synthesis of Difluorinated NR2B NMDA Receptor Antagonists...12 1.3.3 Synthesis of Achiral NR2B NMDA Receptor Antagonists...15 1.4 Biological Results and Conclusions...17 2. Design and Synthesis of Measles Virus Inhibitors...19 2.1 Statement of Purpose...19 2.2 Introduction and background...20 1.2.2 History of Small Molecule Target Development...21 2.3 Results and Discussion...24 2.3.1 MV-F Inhibitors...24 2.3.2 RDRP Inhibitors...25 2.4 Biological Results...28 3. Experimental...29 4. References and Notes...59

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