2025-06-23 カロリンスカ研究所(KI)
カロリンスカ研究所(Karolinska Institutet)は、新しい経口薬が2型糖尿病と肥満治療に有望な効果を示したと発表しました。プレスリリースによると、この薬は血糖値を下げ、脂肪燃焼を促進しながらも、従来の薬剤が引き起こしがちな負の影響を抑える点が特徴です。具体的には、血中グルコース濃度の低下や体脂肪減少が確認され、特殊な副作用も見られず、従来の注射型GLP-1作動薬に匹敵する、安全性と効果が示された模様です。
◆この成果はCell誌の論文として掲載され、研究はKarolinska Institutetのプレスリリースを通じて発表されました。糖尿病・肥満治療薬の経口化が進めば、患者の利便性向上や治療の根本的変革につながる可能性があります。
<関連情報>
- https://news.ki.se/new-drug-for-diabetes-and-obesity-shows-promising-results
- https://www.cell.com/cell/fulltext/S0092-8674(25)00630-0
2型糖尿病および肥満治療のためのGRKに基づくアドレナリン作動薬 GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity
Aikaterini Motso ∙ Benjamin Pelcman ∙ Anastasia Kalinovich ∙ … ∙ Volker M. Lauschke,,, ∙ Shane C. Wright ∙ Tore Bengtsson
Cell Published:June 23, 2025
DOI:https://doi.org/10.1016/j.cell.2025.05.042
Graphical abstract
Highlights
- Chemistry campaign discovers β2AR agonists with different signaling profiles
- Transducer profiling reveals GRK2-biased β2AR activation by designed compounds
- Preclinical evaluation of lead compounds demonstrates efficacy without adverse effects
- Candidate drug is well tolerated in a phase 1 clinical trial in humans
Summary
Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β2 adrenergic receptor (β2AR)-mediated glucose uptake, but β2AR agonists are considered poor clinical candidates for glycemic management due to Gs/cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β2AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β2-receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β2AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.
