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Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
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Identification of novel GLUT inhibitors
Holger Siebeneicher1, Marcus Bauser1, Bernd Buchmann1
1Bayer Pharma AG, Drug Discovery, Medicinal Chemistry 3, Muellerstraße 178, 13353 Berlin, Germany.
Bioorganic & Medicinal Chemistry Letters
|March 8, 2016
Summary
New 1H-pyrazolo[3,4-d]pyrimidines show potent inhibition of glucose transporter 1 (GLUT1). Structure-activity relationship studies identified key molecular features, demonstrating excellent selectivity and promising pharmacokinetic profiles for further development.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Biochemistry
Background:
- Facilitated glucose transporter 1 (GLUT1) plays a crucial role in cellular glucose uptake.
- Dysregulation of GLUT1 is implicated in various diseases, including cancer.
- Targeting GLUT1 presents a therapeutic strategy for diseases characterized by altered glucose metabolism.
Purpose of the Study:
- To identify novel inhibitors of facilitated glucose transporter 1 (GLUT1).
- To establish structure-activity relationships (SAR) for potent GLUT1 inhibitors.
- To evaluate the selectivity and pharmacokinetic properties of identified compounds.
Main Methods:
- High-throughput screening (HTS) to identify initial hits.
- Extensive structure-activity relationship (SAR) studies on the 1H-pyrazolo[3,4-d]pyrimidine scaffold.
- In vitro assays to assess compound potency and selectivity against GLUT1 and GLUT2.
- Initial in vitro and in vivo pharmacokinetic (PK) assessments.
Main Results:
- High-throughput screening identified 1H-pyrazolo[3,4-d]pyrimidines as potent GLUT1 inhibitors.
- Structure-activity relationship studies revealed essential structural motifs: ortho-methoxy substituted benzene, piperazine, and pyrimidine rings.
- Compounds exhibited excellent selectivity against the related glucose transporter GLUT2.
- Initial in vitro and in vivo pharmacokinetic studies demonstrated encouraging drug-like properties.
Conclusions:
- The 1H-pyrazolo[3,4-d]pyrimidine scaffold represents a promising class of GLUT1 inhibitors.
- Key structural features necessary for potent and selective GLUT1 inhibition have been elucidated.
- The identified compounds possess favorable pharmacokinetic characteristics, warranting further investigation for therapeutic applications.
