D-amino acid Lac-Phe analogs gain oral activity against obesity and fatty liver
- The exercise-induced metabolite Lac-Phe suppresses appetite, but its weak metabolic stability limits oral efficacy; the authors introduced a D-amino acid and ran a broad SAR campaign.
- Compound 18 emerged with markedly better metabolic stability and strong appetite suppression after oral dosing.
- It also acted as a potent dual inhibitor of the fatty-acid receptors GPR40 and GPR120.
- In vivo, it reduced obesity and fatty liver, linked to PI3K/Akt/mTOR signaling changes and induced hepatic autophagy.
💡 Points
A D-amino acid is the textbook cure for peptidase liability, so the stability gain is no surprise. What stands out is the pharmacology it uncovered: an appetite suppressor that also inhibits GPR40 and GPR120. Is that the mechanism or an off-target bonus? With no target-engagement data linking the two, I would not let this SAR steer the next round.