Novel Glucagon-like Peptide 1 Receptor Agonists for Treating Type II Diabetes

Abstract

Provided herein are novel glucagon-like peptide-1 receptor agonists, pharmaceutical compositions, use of such compounds in treating type II diabetes, and processes for preparing such compounds.

Important Compound Classes

Title

Glucagon-like Peptide 1 Receptor Agonists

Patent Publication Number

WO 2024/107781 A1

URL: https://patents.google.com/patent/WO2024107781A1/en

Publication Date

May 23, 2024

Priority Application

US 63/425,751

Priority Date

November 16, 2022

Inventors

Chen, Q.; Fields, T.; Ghanekar, P. G.; Hammill, J. T.; Woerly, E. M.

Assignee Company

Eli Lilly and Company, USA

Disease Area

Type II diabetes

Biological Target

Glucagon-like peptide-1

Summary

Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by intestinal enteroendocrine L-cells. GLP-1 induces the release of insulin from beta cells in a glucose-dependent manner. However, GLP-1 is rapidly metabolized so that only a small percentage of the GLP-1 can be utilized to induce insulin secretion. To offset this, GLP-1 receptor (GLP-1R) agonists have been developed to enhance insulin secretion as a treatment for type II diabetes mellitus.

The present application describes a series of novel glucagon-like peptide-1 receptor agonists for the treatment of type II diabetes. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

Ⓧ = phenyl, 5 or 6-membered heteroaryl or pyridone, wherein phenyl, heteroaryl, or pyridone is optionally substituted with one or two R₁;

A = −CH₂O–, −OCH₂–, or −CH₂NH–;

Y₁, Y₂, Y₇, and Y₈ = N, CH or CR₂, wherein no more than one of Y₁, Y₂, Y₇, and Y₈ is N and no more than two of Y₁, Y₂, Y₇, and Y₈ is CR₂;

Y₃, Y₄, Y₅, and Y₆ = N, CH, or CR₂, wherein no more than two of Y₃, Y₄, Y₅, and Y₆ are N and no more than two of Y₃, Y₄, Y₅, and Y₆ are CR₂;

R₃ = C₁–C₄alkoxy optionally substituted with C₁–C₂alkoxy, hydroxy, or C₁–C₃haloalkyl;

Key Structures

Biological Assay

Human GLP-1 receptor HEK293 cell cAMP assay was performed. The compounds described in this application were tested for their ability to inhibit GLP-1R. The GLP-1R EC₅₀ values (nM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for GLP-1R inhibition and the biological data obtained from testing representative examples.

Claims

Total claims: 33

Compound claims: 23

Pharmaceutical composition claims: 1

Method of treatment claims: 4

Method of lowering blood glucose level claims: 1

Use of compound claims: 4

Recent Review Articles

See refs (1−6).

The author declares no competing financial interest.