Dulsat Júlia, Puig de la Bellacasa Raimon, Borrell José I
Grup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain.
Molecules. 2024 Dec 22;29(24):6042. doi: 10.3390/molecules29246042.
In cases in which a rapid metabolism is the cause of an unfavorable pharmacokinetic profile, it is important to determine the Sites of Metabolism (SoMs) of a molecule to introduce the necessary modifications to improve the stability of the compound. The substitution of hydrogen atoms by deuterium atoms has been proposed to ameliorate such properties due to the greater stability of the C-D bonds. , bearing a 2-phenylamino substituent, is a compound previously described by our group with good biological activity as a discoidin domain receptor (DDR2) inhibitor but suffers from low metabolic stability determined in a test with rat-liver microsomes (less than 50% of the initial compound after 60 min). We have obtained the corresponding 2-(penta-deuterophenyl) analog () from aniline-2,3,4,5,6- showing that it has a better metabolic stability than and a higher inhibitory effect on isolated tyrosine kinase receptors but not a better 2D in vitro effect.
在快速代谢是不良药代动力学特征原因的情况下，确定分子的代谢位点（SoM）以引入必要的修饰来提高化合物的稳定性非常重要。由于C-D键具有更高的稳定性，已有人提出用氘原子取代氢原子来改善此类性质。带有2-苯基氨基取代基的[具体化合物名称未给出]是我们小组先前描述的一种化合物，作为盘状结构域受体（DDR2）抑制剂具有良好的生物活性，但在大鼠肝微粒体试验中显示出代谢稳定性低（60分钟后初始化合物剩余不到50%）。我们从苯胺-2,3,4,5,6-获得了相应的2-（五氘代苯基）类似物[具体化合物名称未给出]，表明它比[具体化合物名称未给出]具有更好的代谢稳定性，对分离的酪氨酸激酶受体具有更高的抑制作用，但在二维体外效应方面并无更好表现。
