GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
Bioorg Med Chem Lett. 2010 Oct 1;20(19):5803-6. doi: 10.1016/j.bmcl.2010.07.136. Epub 2010 Aug 5.
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.
在发现 4-(取代氨基)-1-烷基-吡唑并[3,4-b]吡啶-5-甲酰胺是强效和选择性磷酸二酯酶 4B 抑制剂后，[Hamblin, J. N.; Angell, T.; Ballentine, S., 等人。生物有机与医药化学快报。2008, 18, 4237] 进一步研究了 5-位的 SAR。一系列取代的杂环显示出对 PDE4 的良好活性。使用 X 射线晶体学和计算建模进行优化导致发现了 16，其对 LPS 诱导的人外周血单核细胞中 TNF-α 产生的抑制作用低于纳摩尔级。
