Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.
Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 Munich, Germany.
Bioorg Med Chem. 2019 Mar 1;27(5):822-831. doi: 10.1016/j.bmc.2019.01.024. Epub 2019 Jan 24.
To discover new, potent, and selective inhibitors for the murine gamma-aminobutyric acid transporter 4 (mGAT4), the structure-activity relationship (SAR) study of a new cis-alkene analog family based on DDPM-1457 [(S)-2], which previously showed promising inhibitory potency at and subtype selectivity for mGAT4, was conducted. To uncover the importance of the differences between the trans- and the cis-alkene moiety in the spacer, the present publication describes the synthesis of the new compounds via catalytic hydrogenation with Lindlar's catalyst. The biological results collected by the SAR study revealed that analog rac-7j characterized by a four-instead of a three-carbon atom spacer with a cis double bond applying to the majority of the studied compounds displays a surprisingly high potency at mGAT1 (pIC = 6.00 ± 0.04) and at the same time a reasonable potency at mGAT4 (pIC = 4.82).
为了发现新型、高效且选择性的鼠源γ-氨基丁酸转运蛋白 4（mGAT4）抑制剂，我们对基于 DDPM-1457[(S)-2]的新型顺式-烯烃类似物家族进行了构效关系（SAR）研究。此前，[S]-2 在 mGAT4 上表现出有前景的抑制效力和亚型选择性。为了揭示间隔区中环式和反式烯烃部分之间差异的重要性，本研究通过 Lindlar 催化剂催化氢化合成了新的化合物。SAR 研究收集的生物学结果表明，具有顺式双键的新型化合物 rac-7j 的特征是间隔区具有四个而不是三个碳原子，与大多数研究化合物相比，其对 mGAT1（pIC=6.00±0.04）具有惊人的高活性，同时对 mGAT4（pIC=4.82）也具有合理的活性。
