Novel Compounds with Aryl Linkers as Glucagon Receptor Agonists for Treating Type 2 Diabetes Mellitus and Obesity

Abstract

Provided herein are novel compounds with aryl linkers as glucagon receptor agonists, pharmaceutical compositions, use of such compounds in treating type 2 diabetes mellitus and obesity, and processes for preparing such compounds.

Important Compound Classes

Title

Glucagon Receptor Agonists with Aryl Linkers and Their Use as Therapies

Patent Publication Number

WO 2026/006562 A1

URL: https://patents.google.com/patent/WO2026006562A1/en

Publication Date

January 2, 2026

Priority Application

EP 24382692.2

Priority Date

June 27, 2024

Inventors

Agejas Chicharro, F. J.; Anthony, S. M.; Bingham, T. W.; Buchanan, T. L.; Conner, S. E.; Cumming, G. R.; Gatz, M.; Green, S. J.; Knapp, R.; Lineswala, J. P.; Liu, T.; Marimuthu, J.; Martinez-Perez, J. A.; Orizu, I.; Revuelto, A.; Sands, Z.; Schempp, T.; Thapa, B.; Toledo Escribano, M. A.; Tromiczak, E. G.; Yonkunas, M.; Wang, J

Assignee Company

Eli Lilly and Company, USA

Disease Area

Type 2 diabetes and obesity

Biological Target

Glucagon receptor

Summary

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes accounting for approximately 90% of all diabetes. T2DM is characterized by high blood glucose levels caused by insulin resistance. The current standard for care of T2DM includes diet and exercise, and treatment with oral and injectable medications including incretin-based therapies, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and glucose-dependent insulinotropic polypeptide receptor agonists (GIP RA). One of the main risk factors for T2DM is obesity or being overweight

Glucagon is a twenty-nine amino acid peptide which is secreted from the cells of the pancreas into the hepatic portal vein thereby exposing the liver to higher levels of this hormone than nonhepatic tissues. Regulation of the glucagon receptor can play an important role in the treatment of T2DM and obesity.

The present application describes a series of novel compounds with aryl linkers as glucagon receptor agonists for the treatment of type 2 diabetes mellitus and obesity. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R_A1, R_A2, R_A3 and R_A4 = H, C₁–C₁₀ alkyl, CN, C₁–C₁₀ alkoxy, −NR_a1R_b1, −C­(O)­R₈, −SO₂(R)₉, −O–C₃–C₁₀ cycloalkyl, halogen, −C₃–C₁₀ cycloalkyl, and C₂–C₁₀ alkenyl;

ring B = 5 to 10 membered heteroaryl or 4 to 10 membered hetercyclyl ring containing 1 to 3 heteroatoms selected from N, O, and S;

R₄, R_4’, R₅ and R_5′ = H, C₁–C₁₀ alkyl, C₃–C₁₀ cycloalkyl and halogen;

R₆ = aryl, 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S and 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S; and

R₇ = H, C₁–C₁₀ alkyl and halogen.

Key Structures

Biological Assay

Human glucagon (hGCG) receptor (GCGR) functional activity assay using HEK293 clonal cell lines was performed. The compounds described in this application were tested for their ability to inhibit GCGR. The GCGR EC₅₀ (nM) values are shown in the following Table.

Biological Data

The Table below shows representative compounds that were tested for GCGR inhibition. The biological data obtained from testing representative examples are listed in the following Table.

Claims

Total claims: 36

Compound claims: 34

Pharmaceutical composition claims: 1

Method of treatment claims: 1

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The author declares no competing financial interest.