Modulators of KEAP-1 Activity as Potential Therapies for the Treatment of Neurodegenerative Disorders

Important Compound Classes

Title

Small molecule modulators of the BTB domain of KEAP1

Patent Application Number

WO 2019/122265 A1

Publication Date

June 27th, 2019

Priority Application

US 62/609,463

Priority Date

December 22nd, 2017

Inventors

Bartholomeus, J.; Burli, R.; Jarvis, R.; Johnstone, S.; Ostenfeld, T.; Terstiege, I.; Travagli, M.; Turcotte, S.

Assignee Company

Medimmune Limited

Disease Area

Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington disease.

Biological Target

Kelch-like ECH-associated protein 1 (KEAP-1).

Summary

The repressor protein Kelch-like ECH-associated protein 1 (KEAP-1) is a component of the Cullin 3 (CUL3)-based E3 ubiquitin ligase complex. This complex is part of the regulatory system that controls cellular concentration of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a ubiquitously expressed antioxidant transcription factor that induces increased expression of antioxidative and cytoprotective genes when it binds to antioxidant response elements (AREs). Under normal conditions, Nrf2 binds to KEAP-1, thereby controlling the stability and accumulation of cellular Nrf2. Cellular stress, however, induces disassociation of Nrf2 from KEAP-1, allowing it to migrate to the nucleus and bind to AREs. It has been demonstrated that the Nrf2 signaling plays a critical role in protecting cells from oxidative stress. In addition, it has been hypothesized that compounds capable of modulating the activity of this pathway may be useful for the treatment of various neurodegenerative disorders. The present patent application describes compounds capable of modulating Nrf2 signaling by inhibiting binding of Nrf2 to KEAP-1. In addition, the use of the compounds as therapies for treatment of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington disease is described.

Definitions

X is selected from −C(O)– and −SO₂–;

R¹ and R² are each independently is selected from hydrogen and C_1–6 alkyl; or

R¹ and R² taken together with the carbon to which they are attached form a spirocycloalkyl or spiroheterocycloalkyl ring;

R³ is selected from hydroxyl and optionally substituted alkoxy;

R⁴ is selected from optionally substituted aryl and optionally substituted heteroaryl.

Key Structures

Biological Assay

Compounds of the disclosure were screened using HEK-293 cells that have been transfected with ARE transcriptional response element upstream of firefly luciferase. When KEAP-1 is inhibited by compounds of the disclosure, Nrf2 signaling is activated. At the same time, luciferase expression and light emission increases. EC_50s were determined based on concentration-dependent changes in light emission.

Biological Data

Claims

77 Total claims

50 Composition of matter claims

27 Method of use claims

Recent Review Articles

• 1.Basagni F.; Lanni C.; Minarini A.; Rosini M.. Lights and shadows of electrophile signaling: focus on the Nrf2-Keap1 pathway. Future Medicinal Chemistry 2019, 11 ( (7), ), 707–721.
• 2.Pallesen J. S.; Tran K. T.; Bach A.. Noncovalent Small-Molecule Kelch-like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Inhibitors and Their Potential for Targeting Central Nervous System Diseases. Journal of Medicinal Chemistry 2018, 61 ( (18), ), 8088–8103.
• 3.Zhuang C.; Wu Z.; Xing C.; Miao Z.. Small molecules inhibiting Keap1-Nrf2 protein–protein interactions: a novel approach to activate Nrf2 function. MedChemComm 2017, 8 ( (2), ), 286–294.
• 4.Schmoll D.; Engel C. K.; Glombik H.. The Keap1-Nrf2 protein–protein interaction: A suitable target for small molecules, Drug discovery Today: Technologies 2017, 24, 11–17.

The author declares no competing financial interest.