One potential approach for treating obesity is to increase energy expenditure in brown and white adipose tissue. Here we aimed to achieve this outcome by targeting mitochondrial uncoupler compounds selectively to adipose tissue, thus avoiding side effects from uncoupling in other tissues. Selective drug accumulation in adipose tissue has been observed with many lipophilic compounds and dyes. Hence, we explored the feasibility of conjugating uncoupler compounds with a lipophilic C8-hydrocarbon chain via an ether bond. We found that substituting the trifluoromethoxy group in the uncoupler FCCP with a C8-hydrocarbon chain resulted in potent uncoupling activity. Nonetheless, the compound did not elicit therapeutic effects in mice, likely as a consequence of metabolic instability resulting from rapid ether bond cleavage. A lipophilic analog of the uncoupler compound 2,6-dinitrophenol, in which a C8-hydrocarbon chain was conjugated via an ether bond in the para-position (2,6-dinitro-4-(octyloxy)phenol), exhibited increased uncoupling activity compared to the parent compound. However, in vivo pharmacokinetics studies suggested that 2,6-dinitro-4-(octyloxy)phenol was also metabolically unstable. In conclusion, conjugation of a hydrophobic hydrocarbon chain to uncoupler compounds resulted in sustained or improved uncoupling activity. However, an ether bond linkage led to metabolic instability, indicating the need to conjugate lipophilic groups via other chemical bonds.

治疗肥胖的一种潜在方法是增加棕色和白色脂肪组织的能量消耗。在这里，我们的目标是通过选择性地将线粒体解偶联剂化合物靶向脂肪组织来实现这一结果，从而避免在其他组织中解偶联产生的副作用。已经观察到许多亲脂性化合物和染料在脂肪组织中选择性药物积累。因此，我们探索了通过醚键将解偶联剂化合物与亲脂性 C8 烃链缀合的可行性。我们发现用 C8 烃链取代解偶联剂 FCCP 中的三氟甲氧基会产生有效的解偶联活性。尽管如此，该化合物并未对小鼠产生治疗作用，这可能是由于醚键快速断裂导致代谢不稳定的结果。解偶联剂化合物 2,6-二硝基苯酚的亲脂类似物，其中 C8-烃链通过对位的醚键缀合（2,6-二硝基-4-（辛氧基）苯酚），表现出增强的解偶联活性与母体化合物相比。然而，体内药代动力学研究表明，2,6-二硝基-4-(辛氧基)苯酚的代谢也不稳定。总之，疏水性烃链与解偶联剂化合物的缀合导致解偶联活性持续或改善。然而，醚键连接导致代谢不稳定，表明需要通过其他化学键缀合亲脂基团。