Abstract
This highlight describes novel substituted 5H-dibenzo[b,f]azepine compounds and their diverse biological applications. These compounds serve as selective inhibitors of histone deacetylase 6 (HDAC6), and provide methods for the treatment of a broad scope of indications, including Charcot Marie Tooth Disease (CMT).
Important Compound Classes
Title
Heterocyclic compounds as selective HDAC6 inhibitors
Patent Publication Number
WO 2024/192237 A1 URL: https://patents.google.com/patent/WO2024192237A1/en
Publication Date
September 19, 2024
Priority Application
US63/490,128
Priority Date
March 14, 2023
Inventors
Shapiro, G.; Tueckmantel, W.
Assignee Company
Miralinc Pharma, INC. [US/US], 5507 NW 80th Ave, Gainesville, FL 32653, United States
Disease Area
HDAC6-related diseases, such as cancers, strokes, and other cardiovascular conditions
Biological Target
Histone deacetylase 6 (HDAC6).
Summary
Histone deacetylases (HDACs) and histone acetyltransferases (HATs) play crucial role in regulating homeostasis of protein acetylation. Among the 11 HDAC subtypes, the class IIb cytoplasmic enzyme HDAC6 is uniquely involved in various biological processes and regulating cellular functions, such as gene regulation, cell proliferation, and transcription. Due to its important role in physiological processes, HDAC6 has emerged an attractive therapeutic target for many diseases, including cancer and central nervous system (CNS) disorders.
At present, clinically approved HDAC inhibitors exhibit limited specificity and selectivity for HDAC6, often resulting in adverse effects, such as anorexia and gastrointestinal toxicity. Compared to nonspecific inhibitors, selective HDAC6 inhibitors demonstrate superior therapy effect, reduced off-target effect, and improved safety profiles.
This patent introduces a series of substituted heterocyclic 5H-dibenzo[b,f]azepine compounds developed as potent and selective HDAC6 inhibitors, which presents a novel and effective method for treating HDAC6-related indications.
Definitions
X = CH or N;
Y, and Z = CH, CF, or N;
W1 = CH or N;
W2, W3, W4, and W5 = CH, CR1, or N, R1 = C1–C4 alkyl, F, Cl, C1–C4 alkoxy, or CN;
with the proviso that X, Y, Z, W1, W2, W3, W4, W5 cannot be all CH or all N.
Key Structures
Biological Assay
To determine biochemical HDAC enzyme subtype, in vitro HDAC inhibition assays were performed. A fluorescence assay using Ac-GAK(Ac)-AMC as a peptide substrate was conducted to determine the IC50 values and selectivity of the test compounds.
Biological Data
Claims
Total claims: 37
Compound claims: 23
Pharmaceutical composition claims: 1
Method claims: 13
Recent Review Articles
See refs − .
The author declares no competing financial interest.
References
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