Parkinson's disease (PD) is associated with elevated levels of hMAO-B in the brain, and MAO-B has been recognized a successful target for developing anti-PD drugs. Herein we report rasagiline derivatives as novel potent and selective hMAO-B inhibitors. They were designed by employing fragment-based drug design strategy to link rasagiline and hydrophobic fragments, which may target a hydrophobic pocket in the entrance cavity of hMAO-B. Different linkers such as -OCH₂-, -SCH₂-, -OCH₂CH₂-, -OCH₂CH₂O-, -OCH₂CH₂CH₂O- were tried. A promising selective hMAO-B inhibitor D14 with similar inhibitory activity as rasagiline and improved isoform selectivity was yielded. The selectivity profile of compounds reported herein suggests that we can further develop more potent hMAO-B inhibitors with high isoform selectivity through this strategy.

帕金森氏病（PD）与脑中hMAO-B水平升高有关，并且MAO-B已被公认为是开发抗PD药物的成功靶标。在本文中，我们报道雷沙吉兰衍生物作为新型有效的和选择性的hMAO-B抑制剂。通过采用基于片段的药物设计策略来设计它们，以将雷沙吉兰和疏水性片段连接起来，后者可能靶向hMAO-B入口腔中的疏水性口袋。尝试了不同的接头，例如-OCH ₂ -，-SCH ₂ -，-OCH ₂ CH ₂ -，-OCH ₂ CH ₂ O-，-OCH ₂ CH ₂ CH ₂ O-。有希望的选择性hMAO-B抑制剂D14具有与雷沙吉兰相似的抑制活性，并提高了同工型的选择性。本文报道的化合物的选择性特征表明，我们可以通过这种策略进一步开发具有高同工型选择性的更有效的hMAO-B抑制剂。