Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.
Mitchell
Charlotte J
CJ
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. charlotte.j.mitchell@gsk.com
Ballantine
Stuart P
SP
Coe
Diane M
DM
Cook
Caroline M
CM
Delves
Christopher J
CJ
Dowle
Mike D
MD
Edlin
Chris D
CD
Hamblin
J Nicole
JN
Holman
Stuart
S
Johnson
Martin R
MR
Jones
Paul S
PS
Keeling
Sue E
SE
Kranz
Michael
M
Lindvall
Mika
M
Lucas
Fiona S
FS
Neu
Margarete
M
Solanke
Yemisi E
YE
Somers
Don O
DO
Trivedi
Naimisha A
NA
Wiseman
Joanne O
JO
D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D006571:Heterocyclic Compounds; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human