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Hydrolysis of a Ni-Schiff-Base Complex Using Conditions Suitable for Retention of Acid-labile Protecting Groups
Published on: April 6, 2017
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Controlling Plasma Stability of Hydroxamic Acids: A MedChem Toolbox
Paul Hermant1, Damien Bosc1, Catherine Piveteau1
1Univ. Lille Nord de France, INSERM, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, F-59000 Lille, France.
Journal of Medicinal Chemistry
|October 7, 2017
Summary
Hydroxamic acids can be potent drug candidates, but their stability in plasma limits effectiveness. This study identifies key enzymes and provides guidance to improve stability for better in vivo drug development.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Biochemistry
Background:
- Hydroxamic acids are effective zinc chelators for metalloenzyme inhibitors.
- High plasma clearance of some hydroxamic acids reduces their in vivo efficacy despite in vitro potency.
Purpose of the Study:
- To explore structure-plasma stability relationships in hydroxamic acids.
- To identify critical enzymes and pharmacophores affecting hydroxamic acid stability.
- To develop strategies for enhancing hydroxamic acid stability for therapeutic applications.
Main Methods:
- Designed and synthesized a 57-member library of hydroxamic acids.
- Investigated structure-plasma stability relationships.
- Identified key metabolic enzymes responsible for hydroxamic acid degradation.
Main Results:
- Arylesterases and carboxylesterases were identified as the primary enzymes metabolizing hydroxamic acids.
- Structural features influencing plasma stability were elucidated.
- Guidance for improving hydroxamic acid stability was provided.
Conclusions:
- This research offers a medicinal chemistry framework to assess and control hydroxamic acid plasma stability.
- The findings facilitate the development of stable hydroxamic acid-based therapeutics and pharmacological probes.
- The study enables the design of compounds with consistent stability across human and rodent preclinical models.
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