Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Bioorg Med Chem Lett. 2019 Feb 15;29(4):659-663. doi: 10.1016/j.bmcl.2018.12.013. Epub 2018 Dec 6.
Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 6 as a potent Na1.7 inhibitor. Replacement of the C2 furanyl ring of 6 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNa1.7 IC values under 50 nM. Fluorine substitution of the truncated compound 12 led to 34 with improved potency and isoform selectivity. The inverted indole 36 also maintained good activity. Both 34 and 36 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Na1.7 inhibitors to treat pain.
从 Bristol-Myers Squibb 化合物库中筛选 100 种酰基磺酰胺，发现 C3-环己基吲哚 6 是一种有效的 Na1.7 抑制剂。用杂芳基取代 6 的 C2 呋喃环或截断该基团，鉴定出 4 种 hNa1.7 IC 值低于 50 nM 的类似物。截断化合物 12 的氟取代导致 34 具有更好的效力和同工酶选择性。倒置吲哚 36 也保持了良好的活性。化合物 34 和 36 均表现出良好的 CYP 抑制谱、良好的膜通透性和低外排比，因此，它们是寻找有效且选择性的 Na1.7 抑制剂以治疗疼痛的新先导化合物。
