5-Fluoronicotinamide Derivatives as HDAC6 Inhibitors for Treating Heart Diseases

Important Compound Classes

Title

5-Fluoronicotinamide Derivatives and Uses Thereof

Patent Publication Number

WO 2021/067859 A1

Publication Date

April 8, 2021

Priority Application

US 62/910,278

Priority Date

October 3, 2019

Inventors

Mandegar, M. A.; Patel, S.; Bhatt, U.; Ding, P.; Holan, M.; Lee, J.; Li, Y.; Medina, J.; Nerurkar, A.; Seidl, F.; Sperandio, D.; Widjaja, T.; Wang, X.

Assignee Company

Tenaya Therapeutics Inc., USA

Disease Area

Heart Disease

Biological Target

HDAC6

Summary

Histone deacetylases (HDACs) are a class of enzymes with deacetylase activity with a broad range of genomic and nongenomic substrates. There are 11 zinc dependent HDAC enzymes classified based on sequence identity and catalytic activity.

Histone deacetylase inhibitors have been described as therapeutic agents in oncology, neurodegeneration, autoimmune disease, chemotherapy-induced peripheral neuropathy, and cardiac indications. However, many HDAC inhibitors are nonspecific. When administered to humans, these so-called pan-HDAC inhibitors (e.g., SAHA and Panabinostat) exhibit significant adverse effects such as fatigue, nausea, diarrhea, and thrombocytopenia. Thus, there is a need of HDAC inhibitors that selectively target a particular HDAC, such as HDAC6.

HDAC6 belongs to the class IIb enzymes and contains two catalytic domains, a ubiquitin binding domain and a cytoplasmic retention domain. HDAC6-selective inhibitors are known to have reduced cytotoxicity due to the cytoplasmic nature of HDAC6 substrates and reduced effects on nuclear targets and on global transcription.

The present application describes a series of novel 5-fluoronicotinamide derivatives as HDAC6 inhibitors for the treatment of heart diseases. Heart diseases include, but are not limited to, coronary heart disease, cardiomyopathy, endocarditis, congenital cardiovascular defects, congestive heart failure, dilated cardiomyopathy, hypertropic cardiomyopathy, valvular heart disease, myocardial infarction, congestive heart failure, diastolic/systolic heart failure, atrial arrhythmia, ventricular arrhythmia, cardiac valve disease, and ischemia. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = O, NR₄, or CR₄R_4’;

Y is a bond, CR₂R₃ or S(O)₂;

R₁ = H, amido, carbocyclyl, heterocyclyl, aryl, and heteroaryl; and

n = 0 or 1.

Key Structures

Biological Assay

The HDAC6 biochemical assay was performed. The compounds described in this application were tested for their ability to inhibit HDAC6. The HDAC6 IC₅₀ (nM) values are shown in the following Table.

Biological Data

The Table below shows representative compounds were tested for HDAC6 inhibition. The biological data obtained from testing representative examples are listed in the following Table.

Claims

Total claims: 27

Compound claims: 23

Composition claims: 1

Method of treatment claims: 1

Method of improving claims: 1

Method of increasing claims: 1

Recent Review Articles

• 1.Zhang X.; Ma Q.; Wu H.; Khamis M. Y.; Li Y.; Ma L.; Liu H.. J. Med. Chem. 2021, 64, 1362..
• 2.Pulya S.; Amin S. A.; Adhikari N.; Biswas S.; Jha T.; Ghosh B.. Pharmacol. Res. 2021, 163, 105274..
• 3.Diteepeng T.; del Monte F.; Luciani M.. Eur. J. Clin. Invest. 2021, 51, e13504..
• 4.Yang M.; Zhang Y.; Ren J.. Biochim. Biophys. Acta, Mol. Basis Dis. 2020, 1866, 165836..
• 5.Ho T. C. S.; Chan A. H. Y.; Ganesan A.. J. Med. Chem. 2020, 63, 12460..
• 6.Brundel B. J. J. M.; Li J.; Zhang D.. Biochim. Biophys. Acta, Mol. Cell Res. 2020, 1867, 118459..

The author declares no competing financial interest.

Special Issue

Published as part of the ACS Medicinal Chemistry Letters special issue “Epigenetics 2022”.