Since its discovery in 1999, BACE-1, a membrane anchored aspartyl protease expressed primarily in the CNS, has been the target of numerous medicinal chemistry research programs. These efforts have produced highly potent inhibitors with nanomolar affinity and ever-increasing structural complexity. However, only a handful of these molecules have been able to combine in vitro potency with CNS permeability and progressed to the clinic. Herein, we describe a set of novel piperidine-based inhibitors. This investigation culminated with the identification of 43, a highly potent (IC50: 1.5 nM), permeable BACE-1 inhibitor with a low susceptibility to Pgp-mediatedefflux.

中文翻译：

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3,3-二氟-3,4,5,6-四氢吡啶-2-胺：有效和可渗透的BACE-1抑制剂。

自从1999年发现以来，BACE-1（一种主要在CNS中表达的膜锚定的天冬氨酰蛋白酶）已成为许多药物化学研究计划的目标。这些努力已经产生了具有纳摩尔摩尔亲和力和不断增加的结构复杂性的高效抑制剂。但是，这些分子中只有少数能够将体外效能与CNS渗透性结合起来，并进入临床。在本文中，我们描述了一组新型的基于哌啶的抑制剂。这项研究最终鉴定出43种高效，可渗透性BACE-1抑制剂（IC50：1.5 nM），对Pgp介导的外排敏感性低。