Emopamil-Binding Protein Inhibitors for Treating Multiple Sclerosis

Abstract

Provided herein are novel emopamil-binding protein (EBP) inhibitors, their pharmaceutical compositions, the use of such compounds in treating multiple sclerosis, and processes for preparing such compounds.

Important Compound Classes

Title

Emopamil-Binding Protein Inhibitors and Uses Thereof

Patent Publication Number

WO 2023/164063 A1

URL: https://patents.google.com/patent/WO2023164063A1/en

Publication Date

August 31, 2023

Priority Application

US 63/314,095

Priority Date

February 25, 2022

Inventors

Gilfillan, R.; Himmelbauer, M.; Gonzalez Lopez De Turiso, F.; Lin, E. Y. S.; Pattaropong, V.; Xin, Z.; Chen, T. Y.; Jones, J. H.; Bansal, N.

Assignee Company

Biogen Ma Inc., USA

Disease Area

Multiple sclerosis

Biological Target

Emopamil-binding protein (EBP)

Summary

Emopamil-binding protein (EBP) is a Δ8−Δ7 sterol isomerase enzyme which isomerizes the double bond in sterol molecules, moving the double bond from the 8–9 position to the 7–8 position. Specifically, EBP converts either zymostenol to lathosterol or zymosterol to dehydrolathosterol during the biosynthesis of cholesterol. It has been shown that an accumulation of 8–9 unsaturated sterols activates oligodendrocyte formation and remyelination.

Myelin is a lipid-based molecule which forms protective layers (myelin sheathes) around nerve cell axons and insulates the axons. Demyelinating diseases, or myelin-related diseases, are a result of these sheathes being damaged, degraded, or reduced in thickness. The loss of the myelin sheathes disrupts the electronic signals from the brain and can lead to nerve damage, vision loss, numbness, muscle weakness, cognitive decline, loss of motor functions, and other similar symptoms. In some myelin-related diseases, such as multiple sclerosis, a subject’s immune system targets and breaks down their own myelin sheathes. The ability to repair and regenerate the myelin sheathes is key to treating these myelin-related diseases. Due to its function converting 8–9 sterols, inhibition of EBP is a potential target for activating remyelination, as its inhibition leads to an increase of these 8–9 sterol starting materials.

The present application describes a series of novel emopamil-binding protein (EBP) inhibitors for the treatment of multiple sclerosis. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

X = CH₂ or O; Y = CH₂ or O;

R₁ = C_2–6alkyl, Het, or -Z-Het, wherein C_2–6alkyl is optionally substituted with one or more R_A and Het is optionally substituted with one or more R₂;

R₃ = C_1–6alkyl-phenyl, phenyl, 5 or 6-membered monocyclic heteroaryl, or 9 or 10-membered bicyclic heteroaryl, wherein phenyl, 5 or 6-membered monocyclic heteroaryl, and 9 or 10-membered bicyclic heteroaryl is optionally substituted with one or more substituent R₄;

R₅ = H, halo, C_1–3alkyl or C_1–3haloalkyl;

R₆ = H, halo, C_1–3alkyl or C_1–3haloalkyl;

q₁ = 1 or 2;

q₂ = 0 or 1 when Y = CH₂, or q₂ = 2 when Y = O;

p₁ = 1 or 2;

p₂ = 0 or 1 when X = CH₂, or p₂ = 2 when X = O; and

m = 1 or 2; n = 1 or 2.

Key Structures

Biological Assay

The EBP functional assay was performed. The compounds described in this application were tested for their ability to inhibit EBP. The EBP IC₅₀ values (nM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for EBP inhibition and the biological data obtained from testing representative examples. For IC₅₀, + + + means <100 nM.

Claims

Total claims: 72

Compound claims: 67

Pharmaceutical composition claims: 1

Method of treatment claims: 4

Recent Review Articles

See refs (1−5).

The author declares no competing financial interest.