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Bioorg Med Chem Lett. 2012 Jul 15;22(14):4907-11. doi: 10.1016/j.bmcl.2012.04.104. Epub 2012 Apr 30.
Cell-based subset screening of compounds using a Gli transcription factor reporter cell assay and shh stimulated cell differentiation assay identified a series of bisamide compounds as hedgehog pathway inhibitors with good potency. Using a ligand-based optimization strategy, heteroaryl groups were utilized as conformationally restricted amide isosteres replacing one of the amides which significantly increased their potency against SMO and the hedgehog pathway while decreasing activity against p38α kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38α selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics.
基于细胞的化合物亚组筛选，使用 Gli 转录因子报告细胞测定法和 shh 刺激的细胞分化测定法，鉴定出一系列双酰胺化合物作为 hedgehog 途径抑制剂，具有良好的效力。通过基于配体的优化策略，利用杂芳基作为构象受限的酰胺等排体替代酰胺中的一个，这显著提高了它们对 SMO 和 hedgehog 途径的效力，同时降低了对 p38α 激酶的活性。我们在此报告了鉴定出的先进先导化合物，如咪唑 11c 和 11f，它们具有良好的 p38α 选择性、在两种细胞测定中的低纳摩尔效力、优异的理化性质和体内药代动力学。
