Design, synthesis, and biological activity of novel oxazole-based small molecule allosteric GLP-1R agonists

  • Eur J Med Chem. 2026 Nov 15:318:119206. doi: 10.1016/j.ejmech.2026.119206.
Ruifeng Wang  1 ,  Qing Liu  2 ,  Chaoyu Lu  2 ,  Ke Chen  2 ,  Shuihua Liu  2 ,  Liyuan Guo  2 ,  Zhengmin Guo  2 ,  Yunfeng Liu  3 ,  Yi Zhang  4
Affiliations
  • 1. School of Pharmacy, Shanxi Medical University, Taiyuan, 030001, China; Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, Shanxi, 030001, China.
  • 2. School of Pharmacy, Shanxi Medical University, Taiyuan, 030001, China.
  • 3. Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, Shanxi, 030001, China. Electronic address: [email protected].
  • 4. Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, Shanxi, 030001, China; Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi, 030001, China. Electronic address: [email protected].
PMID: 42570411 DOI: 10.1016/j.ejmech.2026.119206
Abstract

Glucagon-like peptide-1 receptor is a key target for Type 2 Diabetes, but current peptide agonists suffer from low oral bioavailability and poor adherence, highlighting the clinical significance of developing small-molecule modulators. Starting from the lead compound V-0219, a series of novel oxazole-containing small-molecule positive allosteric modulators of GLP-1R were designed and synthesized via a scaffold hopping strategy. Systematic structure-activity relationship studies led to the identification of compound 5b, which exhibited superior GLP-1R potentiating activity (44.8% at 10 μM) compared to the lead. Mechanistic studies demonstrated that 5b enhances GLP-1(7-36)- and GLP-1(9-36)-induced cAMP accumulation, directly binds to and stabilizes the GLP-1R protein, and exerts glucose-lowering effects in a GLP-1R-dependent manner. In oral glucose tolerance tests in hGLP-1R knock-in mice, 5b demonstrated modestly improved glucose-lowering efficacy compared to V-0219. In addition, 5b exhibited lower cytotoxicity, favorable metabolic stability in mouse liver microsomes and plasma, and acceptable oral exposure. Collectively, 5b, as a lead compound for orally available small-molecule GLP-1R modulators, warrants further investigation and holds promise for the treatment of Type 2 Diabetes and related metabolic disorders.

Keywords
GLP-1 receptor; Oxazole; Positive allosteric modulator; Type 2 diabetes; hGLP-1R KI mice.
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