Scientific Reports · 12 authors, 9 centres
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This preclinical medicinal chemistry study evaluated NMY1009, an octoxy analogue of the mitochondrial uncoupler FCCP, for adipose tissue targeting. While NMY1009 achieved adipose tissue selective drug accumulation and potent uncoupling activity, it was found to be metabolically unstable in aqueous solution with a half-life of approximately 30 min.
The study explored whether conjugating mitochondrial uncoupler compounds with hydrophobic hydrocarbon chains via an ether bond could achieve adipose tissue selective drug accumulation for obesity treatment. NMY1009 exhibited potent uncoupling activity and achieved adipose tissue selective drug accumulation. However, NMY1009 was metabolically unstable, with a half-life of approximately 30 min in aqueous solution due to spontaneous O-dealkylation at the octoxy ether bond. In contrast, FCCP was stable under the same conditions. Both NMY1009 and FCCP formed adducts with glutathione, but GSH reactivity was unlikely to be the primary route of NMY1009 turnover. The study demonstrated proof of concept for adipose tissue targeting but identified metabolic instability as a key limitation requiring further optimization.
