CN-115361948-B - Methods and compositions for inhibiting dihydroorotate dehydrogenase

Abstract

The present invention discloses 6-substituted-2- ([ 1,1' -biphenyl ] -4-yl) quinoline-4-carboxylic acid analogues which are inhibitors of dihydroorotate dehydrogenase (DHODH) with improved pharmacokinetic properties. The disclosed compounds are useful in the treatment of a variety of disorders and diseases in which inhibition of DHODH may be clinically useful, including cancers, such as hematologic cancers, including Acute Myelogenous Leukemia (AML), graft versus host disease, autoimmune disorders, and disorders associated with T cell proliferation. When administered orally, the disclosed compounds may exhibit turnover kinetics, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of elimination, dominates the pharmacokinetics. The disclosed compounds may exhibit sustained pharmacokinetic profiles rather than immediate release profiles. This abstract is intended as a scanning tool for searching in particular fields and is not intended to limit the present disclosure.

Inventors

• JOHN C BYRD
• Zha De.e.bannite
• Sandipu mahuka wibout
• THOMAS E. GOODWIN
• Ai Lin.hetelin
• Ola A. Egmar
• Taylor Allen Wilson

Assignees

• 俄亥俄州国家创新基金会
• 汉德里克斯学院

Dates

Publication Date

20260505

Application Date

20201226

Priority Date

20191226

Claims (5)

1. 1. A compound selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or a pharmaceutically acceptable salt thereof.
2. 2. The compound of claim 1, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 Or a pharmaceutically acceptable salt thereof.
3. 3. The compound of claim 1, wherein the compound is selected from the group consisting of: 、 、 、 、 Or a pharmaceutically acceptable salt thereof.
4. 4. The compound of any one of claims 1-3, wherein the compound is a pharmaceutically acceptable salt thereof comprising a conjugate base form of the compound and a counterion selected from Li + 、K + 、Na + , ammonium, tetramethyl ammonium, tetraethyl ammonium, fe +2 、Cu +2 、Zn +2 、Mg +2 、Ca +2 、Al +3 、Fe +3 , and combinations thereof.
5. 5. The compound of claim 4, wherein the counterion is Na + .

Description

Methods and compositions for inhibiting dihydroorotate dehydrogenase Cross Reference to Related Applications The present application claims the benefit of U.S. provisional patent application No. 62/953,708 filed on date 26 of 12 in 2019, which provisional patent application is incorporated herein by reference in its entirety. Background Proliferating cells need to supply nucleotides for DNA replication and transcription of genes into RNA, as well as to perform various other metabolic processes. Cells can supply such nucleotides via a de novo nucleotide synthesis pathway. An important step in the de novo synthesis pathway of pyrimidine nucleotides is the oxidation of dihydroorotic acid to form orotic acid. This reaction is catalyzed by dihydroorotate dehydrogenase (DHODH) and this step is one of the rate limiting steps in the pyrimidine nucleotide synthesis pathway. DHODH has subcellular sites in the mitochondrial membrane and uses cytochrome C as an electron acceptor in the electron transport chain to oxidize dihydroorotic acid to orotic acid. Under normal circumstances, the intracellular pool of pyrimidine nucleotides can be replenished by a salvage pathway in which pyrimidine nucleotides are recovered. Although this DHODH-independent mechanism is sufficient for resting lymphocytes, the "activated" and proliferated lymphocytes require a substantial increase in available pyrimidines, thus relying on de novo pyrimidine synthesis. Since orotic acid is an essential intermediate in pyrimidine nucleotide synthesis, and since pyrimidine nucleotides are essential for DNA replication, gene expression and carbohydrate metabolism, inhibition of DHODH enzyme can inhibit cell growth. Furthermore, rapidly proliferating cells require not only pyrimidine for cell growth, but also pyrimidine for protein glycosylation, membrane lipid biosynthesis and chain scission repair (see, e.g., fairbanks et al, j.biol. Chem., 270, pp 29682-29689, 1995). Under such conditions, to meet the increasing demand, a large number of pyrimidine nucleotides must be produced in rapidly proliferating cells. Thus, DHODH inhibitors are attractive candidates for the treatment of proliferative disorders (see, e.g., liu, s. Et al, structure, volume 8: pages 25-31 (2000)), and various studies have shown that DHODH inhibitors can prevent proliferation of tumor cells in certain circumstances (see, e.g., loffer, eur j. Biochem., volume 107: pages 207-215 (1980)). Other conditions in which DHODH inhibitors have been identified as candidates for clinical control of rapid cell division include activated immune cells, diseased skin cells, cancer and infectious agents. Examples of DHODH inhibitors for or being developed for proliferative disorders include buquinate, leflunomide and teriflunomide. Further disclosed are inhibitors of DHODH for the treatment or prophylaxis of autoimmune diseases, immune and inflammatory diseases, angiogenesis-related disorders, viral, bacterial and protozoal diseases. Although DHODH is an attractive target for therapeutic intervention in a variety of clinical conditions, including cancer, the presently described compounds still present significant problems. For example, many of these compounds (including buconazole) suffer from poor bioavailability, in part due to poor water solubility and gastrointestinal absorption. Thus, due to this bioavailability problem, the currently described DHODH inhibitors may have limited pharmaceutical efficacy. Despite advances in research into potent and therapeutically useful DHODH inhibitors, there remains a lack of compounds that are potent and possess appropriate bioavailability characteristics. The present disclosure meets these and other needs. Disclosure of Invention In accordance with the purposes of the present disclosure, as embodied and broadly described herein, the present disclosure relates in one aspect to compounds that are inhibitors of dihydroorotate dehydrogenase (DHODH), and the disclosed compounds have improved pharmacokinetic properties that make them extremely useful for therapeutic intervention in a variety of disorders and diseases (e.g., cancer) in which inhibition of DHODH may be clinically useful. In various aspects, the disclosed compounds are 6-substituted-2- ([ 1,1' -biphenyl ] -4-yl) quinoline-4-carboxylic acid analogs. In further aspects, the disclosed compounds are useful in methods of treating cancer, such as hematologic cancers, including Acute Myelogenous Leukemia (AML), graft versus host disease, and disorders associated with T cell proliferation. In some aspects, the disclosed compounds may exhibit flip-flop (flip-flop) kinetics when administered orally, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of elimination, dominates the pharmacokinetics. Furthermore, the disclosed compounds may exhibit sustained pharmacokinetic profiles rather than immediate release profiles. Disclosed herein are compounds having the formula represented by