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Updated: Jun 7, 2025
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Synthesis of 1,2-Azaborines and the Preparation of Their Protein Complexes with T4 Lysozyme Mutants
Published on: March 25, 2017
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Design and Synthesis of Acyclic Boronic Acid Arginase Inhibitors
Jason D Shields1, Brian M Aquila1, David Emmons1
1Early Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Journal of Medicinal Chemistry
|November 14, 2024
Summary
Researchers developed novel, orally available arginase inhibitors for immuno-oncology. These compounds, designed as prodrugs, show improved oral exposure and potent inhibition, overcoming challenges with traditional boronic acid pharmacophores.
Area of Science:
- Medicinal Chemistry
- Immuno-oncology
- Drug Discovery
Background:
- Arginase is a key target in immuno-oncology.
- Developing orally bioavailable arginase inhibitors is challenging due to the boronic acid pharmacophore requirement.
Purpose of the Study:
- To discover novel, orally bioavailable arginase inhibitors.
- To overcome limitations of existing arginase inhibitors.
Main Methods:
- Structure-based drug design utilizing X-ray crystallography.
- Divergent synthesis featuring an Ireland-Claisen rearrangement.
- Development of prodrug strategies for enhanced oral exposure.
Main Results:
- Achieved a potent arginase inhibitor with an IC50 of 12 nM.
- Synthesized numerous compounds, some crystallized in the arginase 2 active site.
- Prodrugs demonstrated up to 4-fold improved oral exposure.
- Stereochemistry significantly impacted potency and pharmacokinetics.
Conclusions:
- Successful development of potent, orally bioavailable arginase inhibitors.
- Prodrug approach enhances pharmacokinetic properties.
- Structure-activity and structure-property relationships elucidated.
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