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J Med Chem ; 63(1): 382-390, 2020 01 09.
Article in English | MEDLINE | ID: mdl-31850759

ABSTRACT

The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models and human clinical studies. Despite being efficacious, oxytocin is enzymatically unstable and thus considered to be unsuitable for long-term use in patients with obesity. Herein, a series of oxytocin derivatives were engineered through conjugation with fatty acid moieties that are known to exhibit high binding affinities to serum albumin. One analog (OT-12) in particular was shown to be a potent full agonist at the oxytocin receptor (OTR) in vitro with good selectivity and long half-life (24 h) in mice. Furthermore, OT-12 is peripherally restricted, with very limited brain exposure (1/190 of the plasma level). In a diet-induced obesity mouse model, daily subcutaneous administration of OT-12 exhibited more potent anorexigenic and body weight reducing effects than carbetocin. Thus, our results suggest that the long-acting, peripherally restricted OTR agonist may offer potential therapeutic benefits for obesity.


Subject(s)
Anti-Obesity Agents/therapeutic use , Appetite Depressants/therapeutic use , Lipopeptides/therapeutic use , Oxytocin/analogs & derivatives , Oxytocin/therapeutic use , Receptors, Oxytocin/agonists , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Appetite Depressants/chemical synthesis , Appetite Depressants/pharmacokinetics , Body Weight/drug effects , Humans , Lipopeptides/chemical synthesis , Lipopeptides/pharmacokinetics , Male , Mice, Inbred BALB C , Obesity/drug therapy , Oxytocin/pharmacokinetics , Protein Engineering , Weight Loss/drug effects
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