Pyrazolopyridines as potent PDE4B inhibitors: 5-Heterocycle SAR |
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Authors: | 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 |
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Affiliation: | GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom |
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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. |
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