RESUMEN
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).
Asunto(s)
Dihidroorotato Deshidrogenasa , Inhibidores Enzimáticos , Leucemia Mieloide Aguda , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Animales , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/farmacocinética , Descubrimiento de Drogas , Ratas , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Quinolonas/química , Quinolonas/farmacología , Quinolonas/uso terapéutico , Quinolonas/farmacocinética , Quinolonas/síntesis química , Línea Celular Tumoral , Simulación del Acoplamiento MolecularRESUMEN
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.
RESUMEN
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.
Asunto(s)
Cápside , Virus de la Hepatitis B , Cápside/metabolismo , Ensamble de Virus , Antivirales/metabolismo , Proteínas de la Cápside/metabolismo , Replicación ViralRESUMEN
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.
Asunto(s)
Dihidroorotato Deshidrogenasa , Leucemia Mieloide Aguda , Dihidroorotato Deshidrogenasa/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Cápside , Virus de la Hepatitis B , Antivirales/metabolismo , Cápside/metabolismo , Proteínas de la Cápside/metabolismo , Virus de la Hepatitis B/metabolismo , Ensamble de VirusRESUMEN
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.
Asunto(s)
Aminación , Ciclización , Éteres CíclicosRESUMEN
The HBV core protein serves multiple essential functions in the viral life cycle that enable chronic HBV infection to persist, and as such, represents a promising drug target. Modulation of the HBV capsid assembly has shown efficacy in early clinical trials through use of small molecule capsid assembly modulators (CAMs). Herein is described the evolution and SAR of a novel pyrazolo piperidine lead series into advanced oxadiazepinone HBV CAMs.
Asunto(s)
Antivirales/farmacología , Azepinas/farmacología , Proteínas de la Cápside/antagonistas & inhibidores , Virus de la Hepatitis B/efectos de los fármacos , Antivirales/química , Azepinas/química , Proteínas de la Cápside/metabolismo , Relación Dosis-Respuesta a Droga , Virus de la Hepatitis B/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The HBV core protein is a druggable target of interest due to the multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly has shown efficacy in clinical trials. Herein is described the identification and hit to lead SAR of a novel series of pyrazolo piperidine HBV capsid assembly modulators.
Asunto(s)
Antivirales/farmacología , Proteínas de la Cápside/antagonistas & inhibidores , Virus de la Hepatitis B/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Antivirales/química , Proteínas de la Cápside/metabolismo , Relación Dosis-Respuesta a Droga , Virus de la Hepatitis B/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperidinas/química , Pirazoles/química , Relación Estructura-ActividadRESUMEN
Herein is reported a novel screening paradigm PURE (P450s under restriction) for the identification and optimization of hits as part of a hepatitis B virus (HBV) antiviral discovery program. To closely represent in vivo hepatocytes, differentiated HepaRG cells (dHRGs) and primary human hepatocytes (PHHs) were used as the basis for an HBV infection system. However, a significant challenge arose during potency evaluation in using cultured dHRGs and PHHs as screening platforms because, as with hepatocytes in vivo, these cells express active cytochrome P450 enzymes and thus can metabolize test compounds. The observed antiviral effects may be the cumulative result of a dynamic pool of parent compound and metabolites thus confounding structure activity relationship (SAR) interpretation and subsequent optimization design initiatives. We show here that PURE methodology restricts metabolism of HBV-infected dHRGs and PHHs and thus provides highly informative potency data for decision-making on key representative antiviral compounds.
RESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Compuestos de Bifenilo/farmacología , Ácidos Carboxílicos/farmacología , Inhibidores Enzimáticos/farmacología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Animales , Antineoplásicos/química , Compuestos de Bifenilo/química , Ácidos Carboxílicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dihidroorotato Deshidrogenasa , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Humanos , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Relación Estructura-ActividadRESUMEN
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.
RESUMEN
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.
RESUMEN
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.
RESUMEN
The HBV core protein has multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly process has shown clinical efficacy in early clinical trials. Herein is described the SAR exploration of NVR 3-778, the first clinical compound in the sulfonyl carboxamide class.
Asunto(s)
Antivirales/farmacología , Benzamidas/farmacología , Proteínas de la Cápside/antagonistas & inhibidores , Virus de la Hepatitis B/efectos de los fármacos , Piperidinas/farmacología , Antivirales/síntesis química , Antivirales/química , Benzamidas/síntesis química , Benzamidas/química , Proteínas de la Cápside/metabolismo , Relación Dosis-Respuesta a Droga , Virus de la Hepatitis B/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-Actividad , Ensamble de Virus/efectos de los fármacosRESUMEN
NVR 3-778 is the first capsid assembly modulator (CAM) that has demonstrated antiviral activity in hepatitis B virus (HBV)-infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA-containing virus particles with a mean antiviral 50% effective concentration (EC50) of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and a lack of cross-resistance with nucleos(t)ide inhibitors of HBV replication. The combination of NVR 3-778 with nucleos(t)ide analogs in vitro resulted in additive or synergistic antiviral activity. Mutations within the hydrophobic pocket at the dimer-dimer interface of the core protein could confer resistance to NVR 3-778, which is consistent with the ability of the compound to bind to core and to induce capsid assembly. By targeting core, NVR 3-778 inhibits pregenomic RNA encapsidation, viral replication, and the production of HBV DNA- and HBV RNA-containing particles. NVR 3-778 also inhibited de novo infection and viral replication in primary human hepatocytes with EC50 values of 0.81 µM against HBV DNA and between 3.7 and 4.8 µM against the production of HBV antigens and intracellular HBV RNA. NVR 3-778 showed favorable pharmacokinetics and safety in animal species, allowing serum levels in excess of 100 µM to be achieved in mice and, thus, enabling efficacy studies in vivo The overall preclinical profile of NVR 3-778 predicts antiviral activity in vivo and supports its further evaluation for safety, pharmacokinetics, and antiviral activity in HBV-infected patients.
Asunto(s)
Antivirales/farmacología , Benzamidas/farmacología , Cápside/efectos de los fármacos , ADN Viral/antagonistas & inhibidores , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B/tratamiento farmacológico , Piperidinas/farmacología , ARN Viral/antagonistas & inhibidores , Animales , Antígenos Virales/genética , Antígenos Virales/metabolismo , Antivirales/sangre , Antivirales/química , Antivirales/farmacocinética , Benzamidas/sangre , Benzamidas/química , Benzamidas/farmacocinética , Cápside/química , Cápside/metabolismo , ADN Viral/genética , ADN Viral/metabolismo , Evaluación Preclínica de Medicamentos , Femenino , Células Hep G2 , Hepatitis B/virología , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Hepatocitos/virología , Humanos , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Piperidinas/sangre , Piperidinas/química , Piperidinas/farmacocinética , Cultivo Primario de Células , ARN Viral/genética , ARN Viral/metabolismo , Proteínas del Núcleo Viral/antagonistas & inhibidores , Proteínas del Núcleo Viral/genética , Proteínas del Núcleo Viral/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Identification of ligands that selectively activate the M1 muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M1 muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease.
RESUMEN
The current standard of care for treating Alzheimer's disease is acetylcholinesterase inhibitors, which nonselectively increase cholinergic signaling by indirectly enhancing activity of nicotinic and muscarinic receptors. These drugs improve cognitive function in patients, but also produce unwanted side effects that limit their efficacy. In an effort to selectively improve cognition and avoid the cholinergic side effects associated with the standard of care, various efforts have been aimed at developing selective M1 muscarinic receptor activators. In this work, we describe the preclinical and clinical pharmacodynamic effects of the M1 muscarinic receptor-positive allosteric modulator, MK-7622. MK-7622 attenuated the cognitive-impairing effects of the muscarinic receptor antagonist scopolamine and altered quantitative electroencephalography (qEEG) in both rhesus macaque and human. For both scopolamine reversal and qEEG, the effective exposures were similar between species. However, across species the minimum effective exposures to attenuate the scopolamine impairment were lower than for qEEG. Additionally, there were differences in the spectral power changes produced by MK-7622 in rhesus versus human. In sum, these results are the first to demonstrate translation of preclinical cognition and target modulation to clinical effects in humans for a selective M1 muscarinic receptor-positive allosteric modulator.
Asunto(s)
Quinazolinas/farmacología , Receptor Muscarínico M1/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Cognición/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Humanos , Macaca mulatta , Masculino , Quinazolinas/farmacocinética , Investigación Biomédica TraslacionalRESUMEN
In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2R subtype and culminating in the discovery of 23, a highly potent, OX2R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.
Asunto(s)
Antagonistas de los Receptores de Orexina/farmacología , Orexinas/antagonistas & inhibidores , Animales , Electroencefalografía , Electromiografía , Estructura Molecular , Antagonistas de los Receptores de Orexina/química , RatasRESUMEN
While a correlation between blockade of the orexin 2 receptor (OX2R) with either a dual orexin receptor antagonist (DORA) or a selective orexin 2 receptor antagonist (2-SORA) and a decrease of wakefulness is well established, less is known about selective blockade of the orexin 1 receptor (OX1R). Therefore, a highly selective orexin 1 antagonist (1-SORA) with suitable properties to allow in vivo interrogation of OX1R specific pharmacology in preclinical species remains an attractive target. Herein, we describe the discovery of an optimized 1-SORA series in the piperidine ether class. Notably, a 4,4-difluoropiperidine core coupled with a 2-quinoline ether linkage provides OX1R selective compounds. The combination with an azabenzimidazole or imidazopyridine amide substituent leads to analogs 47 and 51 with >625-fold functional selectivity for OX1R over OX2R in rat. Compounds 47 and 51 possess clean off-target profiles and the required pharmacokinetic and physical properties to be useful as 1-SORA tool compounds.
Asunto(s)
Antagonistas de los Receptores de Orexina/química , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Piperidinas/química , Piperidinas/farmacología , Animales , Descubrimiento de Drogas , Humanos , Piperidinas/farmacocinética , Ratas , Ratas Transgénicas , Relación Estructura-ActividadRESUMEN
Orexin signaling, known to modulate arousal and vigilance, is also involved in nociception as orexin neurons project to regions of the brain and spinal cord involved in pain processing, and the administration of orexin peptides can alter pain response in a wide range of preclinical models. Pharmacological treatment with the potent, selective and structurally distinct dual orexin receptor antagonists (ORAs) DORA-12 and DORA-2 significantly reduced pain responses during both phases I and II of the mouse formalin pain model and significantly reversed hyperalgesia in the rat complete Freund's adjuvant pain model, respectively. Significant antinociceptive effects of DORA-12 in the formalin model were also observed in orexin 1 receptor (OX1R) knockout mice, but not orexin 2 receptor (OX2R) or OX1R/OX2R double knockout mice. Mechanical hypersensitivity was significantly reduced with a series of structurally distinct, potent and highly selective ORAs (DORA-2, DORA-12 and DORA-22) in the rat spinal nerve ligation (SNL) injury model of neuropathic pain. Selective pharmacological targeting of OX2R with 2-SORA-7 also reduced pain responses in acute inflammatory (complete Freund's adjuvant) and neuropathic (SNL) rat pain models. Performance on the rotarod test of psychomotor performance and baseline thermal sensitivity were not affected in OX1R/OX2R knockout mice or ORA-treated mice, indicating that the observed pain-reducing effects were not due to sedation or motor deficits. These findings indicate that ORAs have pain-reducing effects across a number of acute and chronic neuropathic preclinical mouse and rat pain models. Further studies on the potential pain-relieving effects of orexin receptor antagonism are warranted.