Pyrazoloheteroaryls: Novel p38α MAP kinase inhibiting scaffolds with oral activity

A test library with three novel p38α inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38α inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.

Graphical abstractA test library with three novel p38α inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituents and scaffolds generated potent p38α inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.Figure optionsDownload full-size imageDownload as PowerPoint slide