Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors.
Basic Information
ID: ALA3745619
Journal: Bioorg Med Chem Lett
Title: Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors.
Authors: Le Roux J, Leriche C, Chamiot-Clerc P, Feutrill J, Halley F, Papin D, Derimay N, Mugler C, Grépin C, Schio L.
Abstract: 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.
CiteXplore: 26681511
DOI: 10.1016/j.bmcl.2015.11.093
Patent ID: ┄