Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors
| Autor: | Philippe Chamiot-Clerc, Christelle Mugler, Nathalie Derimay, John Thomas Feutrill, Jacques Le Roux, Frank Halley, Claudine Grepin, Caroline Leriche, David Papin, Laurent Schio |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular medicine.drug_class Stereochemistry Clinical Biochemistry Protein Data Bank (RCSB PDB) Pharmaceutical Science Carboxamide 010402 general chemistry 01 natural sciences Biochemistry Sulfone chemistry.chemical_compound Structure-Activity Relationship Amide Cell Line Tumor Drug Discovery medicine Cyclic AMP Moiety Humans Sulfones Molecular Biology IC50 010405 organic chemistry Aryl Organic Chemistry Combinatorial chemistry In vitro 0104 chemical sciences Pyrimidines chemistry Aminoquinolines Molecular Medicine Pyrazoles Phosphodiesterase 4 Inhibitors |
| Zdroj: | Bioorganicmedicinal chemistry letters. 26(2) |
| ISSN: | 1464-3405 |
| Popis: | A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency. |
| Databáze: | OpenAIRE |
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