ABSTRACT
Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).
Subject(s)
Dihydroorotate Dehydrogenase , Enzyme Inhibitors , Leukemia, Myeloid, Acute , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Humans , Leukemia, Myeloid, Acute/drug therapy , Animals , Structure-Activity Relationship , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/pharmacokinetics , Drug Discovery , Rats , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacokinetics , Quinolones/chemistry , Quinolones/pharmacology , Quinolones/therapeutic use , Quinolones/pharmacokinetics , Quinolones/chemical synthesis , Cell Line, Tumor , Molecular Docking SimulationABSTRACT
Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that affects many aspects essential to cell proliferation and survival. Recently, DHODH has been identified as a potential target for acute myeloid leukemia therapy. Herein, we describe the identification of potent DHODH inhibitors through a scaffold hopping approach emanating from a fragment screen followed by structure-based drug design to further improve the overall profile and reveal an unexpected novel binding mode. Additionally, these compounds had low P-gp efflux ratios, allowing for applications where exposure to the brain would be required.
ABSTRACT
The protein that forms the inner shell of the HBV virus, known as the capsid core protein, plays a crucial role in allowing chronic HBV infections to persist. Studies have shown that disrupting the assembly of the capsid can effectively combat the virus, and small molecule drugs that target the HBV capsid assembly modulator (CAM) process have been successful in clinical trials. Herein is described a distinct series of di-fluoro azepane CAMs with exceptional potency, pharmacokinetic, and solubility properties.
Subject(s)
Capsid , Hepatitis B virus , Capsid/metabolism , Virus Assembly , Antiviral Agents/metabolism , Capsid Proteins/metabolism , Virus ReplicationABSTRACT
Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered. Two lead compounds, 19 and 29, have potent biochemical and cellular DHODH activity, favorable physicochemical properties, and efficacy in a preclinical model of AML.
Subject(s)
Dihydroorotate Dehydrogenase , Leukemia, Myeloid, Acute , Dihydroorotate Dehydrogenase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Leukemia, Myeloid, Acute/drug therapyABSTRACT
The HBV capsid core protein serves a number of important functions in the viral life cycle enabling chronic HBV infection to persist, and therefore is a promising drug target. Interfering with capsid assembly has shown efficacy in clinical trials with small molecule capsid assembly modulators (CAMs). Herein is described the further optimization of a progressive series of diazepinone HBV CAMs.
Subject(s)
Capsid , Hepatitis B virus , Antiviral Agents/metabolism , Capsid/metabolism , Capsid Proteins/metabolism , Hepatitis B virus/metabolism , Virus AssemblyABSTRACT
Herein, a tandem approach that allows rapid access to the benzomorpholine scaffold is reported. This operationally simple method allows for valuable heterocycles to be isolated in moderate to high yields. The overall transformation consists of an initial C-N coupling, demonstrated using traditional Ullmann or Buchwald-Hartwig conditions, followed by an in situ oxetane ring opening. A range of functionality is tolerated on the aryl ring, and the cyclization exposes a pendant hydroxymethyl substituent, providing opportunities for further functionalization.
Subject(s)
Amination , Cyclization , Ethers, CyclicABSTRACT
Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.
Subject(s)
Antineoplastic Agents/pharmacology , Biphenyl Compounds/pharmacology , Carboxylic Acids/pharmacology , Enzyme Inhibitors/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Biphenyl Compounds/chemistry , Carboxylic Acids/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dihydroorotate Dehydrogenase , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Humans , Mice , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Structure-Activity RelationshipABSTRACT
A convergent method for the rapid preparation of substituted isocoumarins is reported. The transformation takes advantage of a spontaneous intramolecular cyclization that follows the Pd-catalyzed α-arylation of aldehydes with 2-halobenzoic esters. The reaction uses an air-stable, single-component palladium catalyst and provides access to 4-alkylated isocoumarins in one step from commercial starting materials. The applicability of the method using both cyclic and linear ketones as well as transformations of the isocoumarin core is also demonstrated.
ABSTRACT
A tandem one-pot reaction featuring a cross-coupling followed by an intramolecular oxetane ring opening by mild nucleophiles is reported. The overall transformation comprises a carbon-carbon bond formation along with a carbon-heteroatom bond construction providing diverse multicyclic ring systems with a pendant hydroxymethyl handle for further elaboration. This approach constitutes a convergent method for rapid access to various scaffolds. Furthermore, a comparison of computed low-energy conformers is presented to rationalize instances in which cyclization was not observed.
ABSTRACT
Oxetanes have been increasingly used as stable motifs in medicinal chemistry as well as versatile synthetic intermediates. Herein, an intramolecular ring opening of oxetane carboxamides with mild nucleophiles, such as nitrogen heterocycles, is presented. The reaction proceeds under metal-free basic conditions which is highly unusual in ring opening reactions of oxetanes. Amide formation and oxetane ring opening/cyclization in a one-pot approach affords high levels of molecular complexity in a single step from simple, readily available substrates.
ABSTRACT
The first catalytic enantioselective alkynylation of chromones is reported. In this process, chromones are silylated to form silyloxybenzopyrylium ions that lead to silyl enol ethers after Cu-catalyzed alkyne addition using StackPhos as a ligand. The outcome of the reaction is impacted by distal ligand substituents with differing electronic character and it was found that successful reactions could be achieved with different ligand congeners by using different solvents. This sequence enables access to different products by protonation or further functionalization, thus increasing complexity in a divergent manner. The transformation is high yielding over a broad scope to provide a variety of useful chromanones in high enantioselectivity.
Subject(s)
Alkynes/chemical synthesis , Chromones/chemistry , Alkynes/chemistry , Molecular Structure , StereoisomerismABSTRACT
A gold-catalyzed synthesis of cyclic 2-oxodienes from readily prepared propargyl alcohols and the subsequent Diels-Alder reaction are reported. The dehydrative cyclization reactions proceeded smoothly, and the dienes formed in situ were demonstrated to undergo cycloaddition with a variety of dienophiles. This method offers a new strategy for the synthesis of indolocarbazole alkaloids, whereby the convergent synthetic design allows for differentiation between the indole nitrogens.