Pyrazoloheteroaryls: novel p38alpha MAP kinase inhibiting scaffolds with oral activity.
A test library with three novel p38alpha inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38alpha 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.
Revesz
Laszlo
L
Novartis Institutes for BioMedical Research, Global Discovery Chemistry, CH-4002 Basel, Switzerland. laszlo.revesz@novartis.com
Blum
Ernst
E
Di Padova
Franco E
FE
Buhl
Thomas
T
Feifel
Roland
R
Gram
Hermann
H
Hiestand
Peter
P
Manning
Ute
U
Neumann
Ulf
U
Rucklin
Gerard
G
D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011719:Pyrazines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D011720:Pyrazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011719:Pyrazines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; C508194:pyrazolo(3,4-b)pyrazine; C447480:pyrazolo(3,4-b)pyridine; C014175:pyrazolo(3,4-d)pyrimidine; D048308:Mitogen-Activated Protein Kinase 14