Woodrow Michael D, Ballantine Stuart P, Barker Michael D, Clarke Beth J, Dawson John, Dean Tony W, Delves Christopher J, Evans Brian, Gough Sharon L, Guntrip Steven B, Holman Stuart, Holmes Duncan S, Kranz Michael, Lindvaal Mika K, Lucas Fiona S, Neu Margarete, Ranshaw Lisa E, Solanke Yemisi E, Somers Don O, Ward Peter, Wiseman Joanne O
Immuno-Inflammation CEDD Medicinal Chemistry Dept, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK.
Bioorg Med Chem Lett. 2009 Sep 1;19(17):5261-5. doi: 10.1016/j.bmcl.2009.04.012. Epub 2009 Apr 9.
Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.
通过晶体学驱动对从葛兰素史克化合物库相似性搜索中获得的先导化合物进行优化，发现喹啉-3-甲酰胺是磷酸二酯酶4B的高效选择性抑制剂。该系列已优化至GSK256066，这是一种强效的PDE4B抑制剂，它还能抑制脂多糖诱导的人外周血单个核细胞产生肿瘤坏死因子-α，其半数抑制浓度的负对数值为11.1。GSK256066也具有适合吸入给药的特性。
