Charlotte J Mitchell, Stuart P Ballantine, Diane M Coe, Caroline M Cook, Christopher J Delves, Mike D Dowle, Chris D Edlin, J Nicole Hamblin, Stuart Holman, Martin R Johnson, Paul S Jones, Sue E Keeling, Michael Kranz, Mika Lindvall, Fiona S Lucas, Margarete Neu, Yemisi E Solanke, Don O Somers, Naimisha A Trivedi, Joanne O Wiseman
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...
October 1, 2010: Bioorganic & Medicinal Chemistry Letters