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Updated: Jan 10, 2026
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Modification and Functionalization of the Guanidine Group by Tailor-made Precursors
Published on: April 27, 2017
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Linker Modification Enables Control of Key Functional Group Orientation in Macrocycles
Christian Brudy1, Enrico Ruijsenaars2, Christian Meyners1
1Department of Chemistry and Biochemistry Clemens-Schöpf-Institute, Technical University Darmstadt, Peter-Grünberg-Straße 4, 64287 Darmstadt, Germany.
Journal of Medicinal Chemistry
|November 22, 2025
Summary
Macrocyclic drug modifications enhance binding affinity and stability. Small changes, like adding a methyl group, significantly improve properties for targeting FKBP51, a key stress response regulator.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Pharmacology
Background:
- Macrocycles offer unique conformational preorganization for drug development.
- Understanding how scaffold modifications impact preorganization is crucial but poorly explored.
Purpose of the Study:
- To investigate how macrocyclization and linker derivatization influence conformational preorganization.
- To optimize macrocyclic drug properties such as affinity, selectivity, and stability.
- To develop macrocycles targeting FKBP51 for stress response modulation.
Main Methods:
- Synthesized and derivatized macrocyclic compounds.
- Utilized high-resolution cocrystal structures for structural analysis.
- Performed molecular dynamics simulations to understand conformational changes.
- Assessed binding affinity, selectivity, plasma stability, brain permeability, and solubility.
Main Results:
- A single methyl group on the macrocyclic scaffold increased binding affinity up to 10-fold.
- Derivatization of the linker region fine-tuned carbonyl group orientation, improving properties.
- Developed highly ligand-efficient macrocycles with good brain permeability and solubility.
- Demonstrated a promising in vivo profile for FKBP51 inhibition.
Conclusions:
- Minor modifications to macrocyclic scaffolds can significantly enhance drug properties.
- Macrocycles allow for precise tuning of conformational preorganization via linker modifications.
- This approach yields potent and stable macrocyclic drugs with potential therapeutic applications, exemplified by FKBP51 targeting.
![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
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