Abstract
Provided herein are novel compounds as S1P5 modulators, pharmaceutical compositions, use of such compounds in treating neurodegenerative diseases, particularly Alzheimer’s disease, multiple sclerosis, migraine and amyotrophic lateral sclerosis, and processes for preparing such compounds.
Important Compound Classes
Title
Compounds for the Treatment of Neurodegenerative Diseases
Patent Publication Number
WO 2024/019957 A1
Publication Date
January 25, 2024
Priority Application
US 63/390,069
Priority Date
July 18, 2022
Inventors
Brazeau, J.-F.; Ma, R.; Schkeryantz, J. M.; Worm, K.; Papa, P. W.
Assignee Company
Celgene Corporation, USA
Disease Area
Neurodegenerative diseases
Biological Target
Sphingosine-1-phosphate receptor 5
Summary
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that is synthesized by metabolic turnover of sphingolipids in cells and by the extracellular action of a secreted sphingosine kinase. S1P binds to and stimulates members of the endothelial cell differentiation gene family (EDG receptors), which are plasma membrane-localized G protein-coupled receptors. The five members of this family of receptors are S1P1, S1P2, S1P3, S1P4 and S1P5. S1P mediates a wide variety of cellular responses including proliferation, cytoskeletal organization and migration, adherence- and tight junction assembly, and morphogenesis.
S1P5 is primarily expressed in the central nervous system. Specifically, S1P5 is highly expressed in oligodendrocytes (oligodendroglia) and oligodendrocyte progenitor cells. Oligodendrocytes are glial cells that form myelin sheaths (myelin) by binding to the axons of nerve cells. Compounds that bind to S1P5 can modulate the function of S1P5 and are useful in treating neurodegenerative diseases.
The present application describes a series of novel compounds as sphingosine-1-phosphate receptor 5 (S1P5) modulators for the treatment of neurodegenerative diseases, particularly Alzheimer’s disease, multiple sclerosis, migraine and amyotrophic lateral sclerosis. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.
Definitions
L = 
, −CH=CH–, −CH2CH2–, −CH2O–, 
, 
, or a bond;
R1 = halo, CN, C1–C6 alkyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C6 cycloalkyl;
R2 = H, halo, C1–C6 alkyl, C3–C6 cycloalkyl, or C1–C6 haloalkyl;
R3a and R3b = H;
R4 = H, halo, CN, C1–C6 alkyl, C1–C6 haloalkyl, C1–C6 alkoxy, or C3–C6 cycloalkyl;
R6 = H; R7 = C1–C6 alkyl-OH; and x = 0–5.
Key Structures
Biological Assay
The S1P5 GTPγS binding assay was performed. The compounds described in this application were tested for their ability to modulate S1P5. The S1P5 GTPγS binding values (nM) are shown in the following table.
Biological Data
The table below shows representative
compounds that were tested for S1P5 modulation and the biological
data obtained from testing representative examples. For binding: “++++”
means >1 nM to ≤ 10 nM.
Claims
Total claims: 20
Compound claims: 17
Pharmaceutical composition claims: 1
Method of treatment claims: 1
Method of modulation claims: 1
Recent Review Articles
The authors declare no competing financial interest.
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