A bio-organic approach to the design and synthesis of tyrosine kinase inhibitors with multi-modal imaging capabilities.

摘要

Diabetes research has been one of the most active fields for years and will continue to be relevant due to the escalating prevalence of the disease in the US and worldwide.1 Previous research focused on managing and treating the complications of this chronic disease, much of which has been centralized around insulin control. The research described in this thesis concentrated on treating diabetes from a different viewpoint, developing a more integrated approach to treat factors of diabetes, metabolic syndrome and cardiovascular disease. Approaches to improving potent drug candidates involved developing structure activity relationships to determine areas in which improvements can be made. In addition, a prodrug strategy was employed improve upon the pharmacokinetic properties of a novel and potent drug candidate. At this time the research cannot be fully disclosed and will be presented at a later time in patents and journal articles through Novartis Pharmaceuticals.;The up-regulation of epidermal growth factor receptors have been implicated in tumors of numerous cancers including pancreatic, breast, and non-small cell lung. Despite the efficacy of the three FDA approved tyrosine kinase inhibitors (TKI), success has been hampered in part because it is currently difficult to quantitate the expression of epidermal growth factor receptor (EGFR) prior to treatment. Noninvasive imaging agents that provide such data could enable personalized medicine. As a result, a medicinal strategy was employed to develop and synthesize a non-invasive diagnostic TKI for the imaging of tissue function. This agent can provide evidence of drug efficacy, allow for disease monitoring, help predict optimal dosage, and lead to selection of patients who are likely to be responsive to the particular therapeutic approach. The proposed diagnostic tool could allow doctors and clinicians to perform a more rapid and comprehensive evaluation of the cancer patient's sensitivity toward the ErbB receptor therapy.