An updated patent review of small molecule glucagon receptor antagonists (2020-2024).

Introduction: The glucagon receptor (GCGR) plays a pivotal role in diabetes management. While small molecule GCGR antagonists (GCGRAs) offer several advantages, including glycemic control, oral bioavailability, and cost-effectiveness, their clinical development is hampered by safety concerns. Recent structural and mechanistic insights have elucidated ligand binding and biased signaling and informed the rational design of GCGRAs.

Areas covered: This review presents an overview of small molecule GCGRAs between 2020 and 2024, drawing information from existing patents, peer-reviewed literature, and clinical data retrieved from the PubMed, Web of Science, SciFinder, and Derwent Innovation databases.

Expert opinion: In this observation period, innovation ownership shifted from pharmaceutical companies to academic institutions, which are emerging as key applicants for novel chemotypes. Such a significant shift reflects a broader divergence in innovation strategies, with academia increasingly exploring new chemotypes supported by deep learning and virtual screening, while companies focus on maintaining and optimizing established scaffolds. Furthermore, advances in structural and mechanistic studies have clarified ligand binding and biased signaling, informing the rational design of high-specificity, high-affinity GCGRAs. However, clinical investigations are warranted to assess whether these compounds can overcome current developmental bottlenecks, restore glucose homeostasis, and address safety concerns.