Important Compound Classes
Title
Indazole and Benzoisoxazole Dihydroorotate Dehydrogenase Inhibitors
Patent Publication Number
WO 2021/240424 A1
Publication Date
December 2, 2021
Priority Application
US 63/031,815
Priority Date
May 29, 2020
Inventors
Kuduk, S.; Zhang, X.
Assignee Company
Janssen Biotech Inc., USA
Disease Area
Acute myelogenous leukemia (AML)
Biological Target
Dihydroorotate dehydrogenase (DHODH)
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 nucleotide synthesis, but also the biosynthesis of glycoproteins and phospholipids. 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 indazole and benzoisoxazole compounds as DHODH inhibitors that are useful for treatment of cancer, autoimmune, and inflammatory diseases, particularly for the treatment of AML. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
Q = O or N-Rc, wherein Rc is H, CH3, or CH(CH3)3;
R3 = O-R4 or NH-R4; and
R5 = H, C1-3alkyl, F, or Cl.
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) are shown in the table below.
Biological Data
The table below shows representative compounds that were tested for DHODH
and MOLM-13 inhibition. The biological data obtained from testing the
representative examples are listed in the following table.
Claims
Total claims: 14
Compound claims: 7
Pharmaceutical composition claims: 1
Method of treatment claims: 6
The author declares no competing financial interest.
References
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