Li Hui, Linton Angelica, Tatlock John, Gonzalez Javier, Borchardt Allen, Abreo Mel, Jewell Tanya, Patel Leena, Drowns Matthew, Ludlum Sarah, Goble Mike, Yang Michele, Blazel Julie, Rahavendran Ravi, Skor Heather, Shi Stephanie, Lewis Cristina, Fuhrman Shella
Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA.
J Med Chem. 2007 Aug 23;50(17):3969-72. doi: 10.1021/jm0704447. Epub 2007 Jul 21.
The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.
本文介绍了一类新型碳连接二氢吡喃酮作为变构丙型肝炎病毒NS5B聚合酶抑制剂的发现和优化过程。用碳取代硫连接原子降低了化合物的酸度，并显著提高了细胞渗透性。进一步的构效关系（SAR）研究导致鉴定出化合物，如23和24，它们在基于细胞的复制子试验中具有显著改善的抗病毒活性和良好的药代动力学特性。
