Novel Galectin-3 Inhibitors for Treating Fibrosis

Important Compound Classes

Title

Small Molecule Inhibitors of Galectin-3

Patent Publication Number

WO 2020/210308 A1

Publication Date

October 15, 2020

Priority Application

US 62/831,753

Priority Date

April 10, 2019

Inventors

Liu, C.; Feng, J.; Devasthale, P.; Murugesan, N.; Ellsworth, B. A.; Regueiro-Ren, A.; Nara, S. J.; Jalagam, P. R.; Panda, M.

Assignee Company

Bristol-Myers Squibb Company, USA

Disease Area

Fibrosis

Biological Target

Galectin-3

Summary

Galectin-3 (Gal-3) is a β-galactoside binding lectin of ∼30 kDa that is involved in the regulation of inflammatory and fibrotic processes. Under uncontrolled inflammation and profibrotic condition, Gal-3 promotes fibroblast proliferation and transformation and mediates collagen production.

Gal-3 is localized in many cellular locations such as the cytoplasm, nucleus, and cell surface. Gal-3 is also secreted by various cell types, mainly macrophages and monocytes, into the bloodstream. Gal-3 is involved in the development of the fibrotic process in multiple organs such as lung and kidney. Gal-3 has also been identified as a biomarker for heart failure. Modulation of Gal-3 can be used in the treatment of cancer. Recently, Gal-3 inhibitors have proven to have positive effects when used in combination immunotherapy.

The present application describes a series of novel small-molecule galectin-3 inhibitors of Formula (I) or Formula (II), and they are useful for the treatment of fibrosis. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = −C(O)–, −CH₂–, and −CH₂C(O)–;

Ar₁ = phenyl or naphthyl; wherein each ring moiety is substituted with 1 to 5 substituents selected from cyano, halogen, C_1–4 alkyl, C_1–4 alkoxy, C_1–4 haloalkyl, and C_1–4 haloalkoxy;

R₁ = H, C_1–4 alkyl, and, C_1–4 haloalkyl;

R₂ = H, or C_1–4 alkyl;

R₃ = Ar₂, −(CH₂)_1–2Ar₂, and −CH₂CH₂NR₄Ar₂;

Ar₂ = phenyl, , and heteroaryl including from 5 to 10 ring atoms, wherein from 1 to 4 ring atoms are each independently selected from N, N(R₅), O, and S; and wherein each ring moiety is substituted with 0 to 4 substituents selected from OH, cyano, halogen, C_1–4 alkyl, C_1–4 alkoxy, C_1–4 haloalkyl, C_1–4 haloalkoxy, −N(C_1–4 alkyl)₂, −SO₂(C_1–4 alkyl), −OPh, −OBn, C_3–6 cycloalkyl, and phenyl substituted with 0 to 1 substituents selected from cyano, halogen, C_1–4 alkyl, C_1–4 alkoxy, C_1–4 haloalkyl, C_1–4 haloalkoxy, −NH₂, −NH(C_1–4 alkyl), and −N(C_1–4 alkyl)₂.

R₄ = H, or C_1–4 alkyl; and

R₅ = H, or C_1–4 alkyl.

Key Structures

Biological Assay

The Gal-3 HTRF assay was performed. The compounds described in this application were tested for their ability to inhibit Gal-3. The hGal-3 HTRF half-maximal inhibitory concentration (IC₅₀) (μM) values are shown in the following Table.

Biological Data

The Table below shows representative compounds that were tested for Gal-3 inhibition. The biological data obtained from testing these representative examples are listed in the following Table.

Claims

Total claims: 11

Compound claims: 8

Composition claims: 1

Use for treatment claims: 2

Recent Review Articles

• 1.Cao Z.; Yu X.; Leng P.. Biomed. Pharmacother. 2021, 133, 111066.
• 2.Argueso P.Curr. Opin. Physiol. 2021, 19, 17.
• 3.Setayesh T.; Colquhoun S. D.; Wan Y. Y.. Liver Res. 2020, 4, 173.
• 4.Srejovic I.; Selakovic D.; Jovicic N.; Jakovljevic V.; Lukic M. L.; Rosic G.. Biomolecules 2020, 10, 798.
• 5.Gu M.; Mei X.; Zhao Y.. Eur. J. Pharmacol. 2020, 881, 173213.
• 6.George P. M.; Wells A. U.; Jenkins R. G.. Lancet Respir. Med. 2020, 8, 807.

The author declares no competing financial interest.