Medicinal Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, Unit 310 Darwin Building , Cambridge CB4 0WG , United Kingdom.
J Med Chem. 2018 Oct 11;61(19):8934-8943. doi: 10.1021/acs.jmedchem.8b01148. Epub 2018 Sep 20.
In this article, we report our investigation of a phenomenon by which bridging morpholines across the ring with one-carbon tethers leads to a counterintuitive reduction in lipophilicity. This effect was also found to occur in piperazines and piperidines and lowered the measured log D of the bridged molecules by as much as -0.8 relative to their unbridged counterparts. As lowering lipophilicity without introducing additional heteroatoms can be desirable, we believe this potentially provides a useful tactic to improve the drug-like properties of molecules containing morpholine-, piperazine-, and piperidine-like motifs.
在本文中，我们报告了一项研究结果，即通过在环上用单碳链桥接吗啉导致脂溶性出人意料地降低。这种效应也在哌嗪和哌啶中发现，使 bridged 分子的实测 log D 比其无桥接对应物低了多达-0.8。由于降低脂溶性而不引入额外的杂原子可能是可取的，我们认为这为改善含有吗啉、哌嗪和哌啶类似结构的分子的类药性提供了一种有用的策略。
