Discovery Sciences Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, Beerse B-2340, Belgium.
Discovery Sciences Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, Beerse B-2340, Belgium.
Bioorg Med Chem Lett. 2020 Apr 15;30(8):126999. doi: 10.1016/j.bmcl.2020.126999. Epub 2020 Jan 27.
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 (IC: 1.5 nM), permeable BACE-1 inhibitor with a low susceptibility to Pgp-mediatedefflux.
自 1999 年发现以来，BACE-1 作为一种主要在中枢神经系统表达的膜锚定天冬氨酸蛋白酶，一直是众多药物化学研究项目的目标。这些努力产生了具有纳摩尔亲和力和不断增加的结构复杂性的高度有效的抑制剂。然而，只有少数这些分子能够将体外效力与中枢神经系统通透性结合起来并推进到临床。在此，我们描述了一组新型的哌啶基抑制剂。这项研究的最终成果是鉴定出 43，一种高活性（IC：1.5 nM）、可渗透的 BACE-1 抑制剂，对 Pgp 介导的外排具有低敏感性。
