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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
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Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic
Allyn T Londregan1, Liuqing Wei1, Jun Xiao1
1Pfizer Medicinal Chemistry , Groton , Connecticut 06340 , United States.
Journal of Medicinal Chemistry
|June 8, 2018
Summary
Researchers optimized small molecule inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA translation. Optimized compounds 7l and 7n show improved safety and efficacy for in vivo studies.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Drug Discovery
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol metabolism.
- Inhibiting PCSK9 mRNA translation offers a therapeutic strategy for managing hypercholesterolemia.
- Developing small molecule inhibitors with improved potency and safety profiles is essential.
Purpose of the Study:
- To optimize a novel class of small molecule PCSK9 mRNA translation inhibitors.
- To enhance the potency, physicochemical properties, and off-target pharmacology of initial hit compounds.
- To identify drug candidates suitable for in vivo evaluation and assess their safety profiles.
Main Methods:
- Structure-activity relationship (SAR) studies involving modifications to key regions of the molecule.
- Development of synthetic routes to overcome challenges in constructing the congested amide center.
- In vitro and in vivo pharmacological assessments, including toxicology studies.
Main Results:
- Optimization efforts led to compounds 7l and 7n with improved overall profiles.
- Compound 7l demonstrated a superior safety profile compared to the lead compound 7f in a 14-day toxicology study.
- Hypothesized mechanism for improved safety involves reduced binding to nontranslating ribosomes and enhanced transcript selectivity.
Conclusions:
- Successful optimization of PCSK9 mRNA translation inhibitors resulted in promising candidates for further development.
- Compound 7l exhibits an improved safety profile, potentially due to enhanced transcript selectivity and reduced off-target ribosome binding.
- These findings support the potential of this new class of inhibitors for therapeutic applications in hypercholesterolemia.
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