Thienopyrimidines as β3-adrenoceptor agonists: hit-to-lead optimization
Stefan Tasler1, Roland Baumgartner, Astrid Ammendola
14SC AG, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany. stefan.tasler@4sc.com
Bioorganic & Medicinal Chemistry Letters
|September 14, 2010
Summary
Researchers developed a novel human β3-adrenoceptor (β3-AR) agonist using a thienopyrimidine scaffold. This compound shows excellent cellular activity and selectivity, indicating potential therapeutic applications.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Discovery
Background:
- The β3-adrenoceptor (β3-AR) is a key target for various physiological processes.
- Development of selective β3-AR agonists is crucial for therapeutic interventions with reduced side effects.
Purpose of the Study:
- To identify and optimize novel human β3-AR agonists.
- To develop a compound with high potency, selectivity, and a favorable safety profile.
Main Methods:
- Virtual High-Throughput Screening (vHTS) using pharmacophore alignment.
- Optimization of an aryloxypropanolamine scaffold containing a thienopyrimidine moiety.
- In vitro cellular assays to determine activity (EC50) and selectivity against β1- and β2-adrenoceptors.
Main Results:
- A lead compound based on the thienopyrimidine scaffold was identified.
- The lead compound demonstrated excellent cellular activity with an EC50 of 20 pM.
- High selectivity was observed over human β1- and β2-adrenoceptors, alongside a promising safety profile.
Conclusions:
- The optimized thienopyrimidine-based aryloxypropanolamine is a potent and selective human β3-AR agonist.
- This lead compound represents a promising candidate for further preclinical development.
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