title: Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.
abstract: 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.
authors: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. charlotte.j.mitchell@gsk.com
authors: Charlotte J
authors: CJ
authors: Mitchell
authors: Stuart P
authors: SP
authors: Ballantine
authors: Diane M
authors: DM
authors: Coe
authors: Caroline M
authors: CM
authors: Cook
authors: Christopher J
authors: CJ
authors: Delves
authors: Mike D
authors: MD
authors: Dowle
authors: Chris D
authors: CD
authors: Edlin
authors: J Nicole
authors: JN
authors: Hamblin
authors: Stuart
authors: S
authors: Holman
authors: Martin R
authors: MR
authors: Johnson
authors: Paul S
authors: PS
authors: Jones
authors: Sue E
authors: SE
authors: Keeling
authors: Michael
authors: M
authors: Kranz
authors: Mika
authors: M
authors: Lindvall
authors: Fiona S
authors: FS
authors: Lucas
authors: Margarete
authors: M
authors: Neu
authors: Yemisi E
authors: YE
authors: Solanke
authors: Don O
authors: DO
authors: Somers
authors: Naimisha A
authors: NA
authors: Trivedi
authors: Joanne O
authors: JO
authors: Wiseman
mesh_terms: 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
chemical_list: 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