Boezio Alessandro A, Andrews Kristin, Boezio Christiane, Chu-Moyer Margaret, Copeland Katrina W, DiMauro Erin F, Foti Robert S, Fremeau Robert T, Gao Hua, Geuns-Meyer Stephanie, Graceffa Russell F, Gunaydin Hakan, Huang Hongbing, La Daniel S, Ligutti Joseph, Moyer Bryan D, Peterson Emily A, Yu Violeta, Weiss Matthew M
Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States.
Amgen, Inc., 360 Binney Street, Cambridge, MA 02142, United States.
Bioorg Med Chem Lett. 2018 Jun 15;28(11):2103-2108. doi: 10.1016/j.bmcl.2018.04.035. Epub 2018 Apr 17.
Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit Na1.7 and demonstrate high levels of selectivity over other Na isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective Na1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over Na1.5 and favorable pharmacokinetics in rodents.
最近，有报道称已鉴定出几类能有效抑制Na1.7且对其他钠亚型表现出高度选择性的芳基磺酰胺和酰基磺酰胺。这些抑制剂的完全可电离性质已被证明是观察到的效力和亚型选择性药效团的重要组成部分。然而，这种功能的要求给优化具有类药物性质和最小脱靶活性的抑制剂带来了挑战。为了克服这些挑战，我们着手开发一种口服生物可利用的、选择性Na1.7抑制剂，该抑制剂缺乏这些酸性官能团。在此，我们报告了一系列新型抑制剂的发现，其中三唑砜被设计用作酰基磺酰胺的生物电子等排体。这项工作最终得到了一系列有效的抑制剂，这些抑制剂对Na1.5表现出良好的选择性，并且在啮齿动物中具有良好的药代动力学。
