Abstract
Provided herein are novel dihydroorotate dehydrogenase (DHODH) inhibitors, pharmaceutical compositions, use of such compounds in treating acute myelogenous leukemia (AML), and processes for preparing such compounds.
Important Compound Classes
Title
Dihydroorotate Dehydrogenase Inhibitors
Patent Publication Number
WO 2022/070068 A1
Publication Date
April 7, 2022
Priority Application
US 63/085,313
Priority Date
September 30, 2020
Inventors
Deratt, L.; Kuduk, S.; Zhang, Z.
Assignee Company
Janssen Biotech Inc., USA
Disease Area
Acute myelogenous leukemia (AML)
Biological Target
Dihydroorotate dehydrogenase
Summary
Acute myelogenous leukemia (AML) is a clonal disease of the blood and bone marrow resulting from mutations that occur in normal hematopoietic stem cells. AML is a heterogeneous disease in that it presents with a range of cytogenetic, morphological, and immunophenotypic features and is characterized by an accumulation of clonal, abnormal myeloid progenitor cells, known as myeloblasts. These cells demonstrate disruption of normal myeloid differentiation and excessive proliferation, resulting in the decreased formation of hematopoietic cells.
Dihydroorotate dehydrogenase (DHODH) is a flavin mononucleotide (FMN) flavoprotein located in the inner mitochondrial membrane that catalyzes the oxidation of dihydroorotate to orotate, the fourth step in the de novo pyrimidine biosynthesis pathway. Inhibition of DHODH decreases the synthesis of pyrimidines, important precursors for not only nucleotide synthesis but also glycoprotein and phospholipid biosynthesis. DHODH inhibition drives AML differentiation in vitro and results in dose-dependent antileukemic effects, decreased leukemic stem cells, and prolonged survival in vivo. Small-molecule DHODH inhibitors mediate antiproliferative activity against AML cells with concomitant cell cycle arrest and induction of apoptosis.
The present application describes a series of novel DHODH inhibitors which are useful for treatment of cancer, autoimmune, and inflammatory diseases, particularly for the treatment of acute myelogenous leukemia (AML). Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
X = CH or N; Y = CH or N, wherein when
X is N, then Y is CH;
Key Structures
Biological Assay
In vitro DHODH enzymatic assay and in vitro MOLM-13 cellular assay were performed. The compounds described in this application were tested for their ability to inhibit DHODH and MOLM-13. The DHODH IC50 (nM) and MOLM-13 IC50 (nM) values are shown in the table below .
Biological Data
The following table shows representative
compounds that were tested for DHODH and MOLM-13 inhibition and the
biological data obtained from testing representative examples.
Claims
Total claims: 32
Compound claims: 23
Pharmaceutical composition claims: 2
Method of treatment claims: 7
Recent Review Articles
The author declares no competing financial interest.
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