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

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $11,751

## Abstract

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.

## Key facts

- **NIH application ID:** 10348159
- **Project number:** 5F31GM140677-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** James Lester Collins
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $11,751
- **Award type:** 5
- **Project period:** 2021-05-01 → 2022-05-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348159

## Citation

> US National Institutes of Health, RePORTER application 10348159, Improving Metabolic Stability Profiles in Kinase Inhibitor Development Through the Use of 1-Aminonorbornanes as Aniline Bioisosteres (5F31GM140677-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348159. Licensed CC0.

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