Improving Metabolic Stability Profiles in Kinase Inhibitor Development Through the Use of 1-Aminonorbornanes as Aniline Bioisosteres

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Improving Metabolic Stability Profiles in Kinase Inhibitor Development Through the Use of 1- Aminonorbornanes as Aniline Bioisosteres Abstract The proposed work focuses on the development of 1-aminonorbornanes and demonstration that these systems can serve as metabolically-inert aniline bioisosteres. Toxicity profiles, particularly hepatotoxicity, requiring black box warnings are common among FDA-approved tyrosine kinase inhibitors. Anilines, although they are commonly used in the pharmaceutical industry, are often easily oxidized by CYP450s. Formation of reactive intermediates upon oxidation often times leads to adverse drug-drug interactions and idiosyncratic toxicities. Unfortunately, there are currently no clear isosteres for anilines, forcing medicinal chemists to continually use these motifs despite the known proclivity to metabolism-derived off-target toxicity. A photochemical strategy to readily synthesize 1-aminonorbornanes has been developed and published. Preliminary results suggest the 1- aminonorbornane motifs occupy similar chemical space to anilines, despite their drastic structural difference. These results have served as the initial proof-of-concept that the saturated carbocyclic framework of 1- aminonorboranes can serve as a reliable aniline bioisostere. This preliminary evidence has optimally-positioned this project to implement our synthetic designs and discoveries into disruptive translational advances. This will be accomplished through the development of novel 1-aminonorbornane-based analogs of the oncolytic kinase inhibitors, lapatinib and erlotinib. These isosteric analogs are anticipated to offer analogous anti-neoplastic efficacy while avoiding the adverse metabolic events that have limited the utility of these and other cancer chemotherapies. This work will thus validate the utility of 1-aminonorbornanes as aniline bioisosteres and provide the momentum necessary to shift the drug development paradigm from risk-laden aromatic motifs to better- tolerated, saturated building blocks.