Synthesis of Leukotriene A4 Hydrolase (LTA4H) Aminopeptidase (AP) Modulators Using Cross-Coupling Reactions and Synthesis of Oxetanyl Peptidomimetics



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The leukotriene A4 hydrolase (LTA4H) enzyme is a potential biological target for treatment of inflammatory diseases. Most drug discovery efforts have focused on inhibition of the epoxide hydrolase (EH) activity but this strategy has failed to show promising results in human clinical trials. Activation of LTA4H’s aminopeptidase (AP) activity by 4-methoxydiphenylmethane (4MDM) was shown to resolve inflammation in chronic obstructive pulmonary disease (COPD) mouse models, providing an alternative strategy for treatment of inflammatory diseases. The bulk of this work focuses on the synthesis and enzyme kinetic evaluation of novel LTA4H AP modulators. The goal was to find a superior activator of the AP activity of LTA4H compared to 4MDM. A smaller portion of this work is dedicated to the synthesis of oxetanyl peptidomimetics, which are an emerging class of peptidomimetics that have potential applications in drug discovery.