The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron

  • Sci Transl Med. 2024 Dec 18;16(778):eadp5765. doi: 10.1126/scitranslmed.adp5765.
Kyle W Sloop  1 ,  Amy L Cox  1 ,  David B Wainscott  2 ,  Alex White  2 ,  Brian A Droz  1 ,  Cynthia Stutsman  1 ,  Aaron D Showalter  1 ,  Todd M Suter  1 ,  James D Dunbar  1 ,  Brandy M Snider  1 ,  Libbey S O'Farrell  1 ,  Natalie Hewitt  2 ,  J Craig Ruble  3 ,  Leah R Padgett  2 ,  Eric M Woerly  3 ,  Jeffrey A Peterson  4 ,  Tamer Coskun  1 ,  Zhaomin Liu  5 ,  David E Coutant  5 ,  Minrong Ai  1 ,  Paul J Emmerson  1 ,  Panjamaporn Sangwung  2 ,  Francis S Willard  2
Affiliations
  • 1. Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
  • 2. Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indianapolis, IN 46285, USA.
  • 3. Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
  • 4. Synthetic Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
  • 5. Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
PMID: 39693407 DOI: 10.1126/scitranslmed.adp5765
Abstract

Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the Metabolic Disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and Other NPAs. Competition binding experiments using either [125I]GLP-1(7-36)NH2 or [3H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant (Ki) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor Ki value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R (Glp1rS33W) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in Glp1rS33W rats enabled studies showing weight loss in Animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of Other peptide receptors with NPAs.

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