Shionogi Pharmaceutical Research Center, Shionogi and Co., Ltd. , 3-1-1, Osaka 561-0825, Japan.
J Med Chem. 2013 Feb 14;56(3):1124-35. doi: 10.1021/jm301550c. Epub 2013 Jan 22.
This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoyl pyridone analogues to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in standard antiviral assays. An additional hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clinically relevant resistant viruses. These findings led to additional cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors to address remaining issues and deliver potential clinical candidates. The tricyclic carbamoyl pyridone derivatives described herein served as the immediate leads in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation.
这项工作是我们最初发现强效单环氨甲酰吡啶酮人类免疫缺陷病毒 1 型（HIV-1）整合酶抑制剂的延续，该抑制剂显示出良好的抗病毒和药代动力学特性。我们在此报告了一系列双环氨甲酰吡啶酮类似物，以解决我们最初的 SAR 研究中出现的构象问题。通过对核心单元的这种修饰，成功地在标准抗病毒测定中实现了低纳摩尔效力。在双环支架上增加一个额外的羟基取代基，显著提高了对临床相关耐药病毒的抗病毒功效。这些发现促使我们进一步将裸露的羟基进行环化连接，得到了三环氨甲酰吡啶酮抑制剂，以解决剩余的问题，并提供有潜力的临床候选药物。本文所述的三环氨甲酰吡啶酮衍生物是下一代整合酶抑制剂多替拉韦（dolutegravir）的直接先导化合物，目前正在进行后期临床评估。
