RESUMEN
BACKGROUND: The woods of trees of the genus Dalbergia are a frequent cause of allergic contact dermatitis. OBJECTIVES: To describe the different patterns of symptoms and sensitisation to woods of the genus Dalbergia in four patients whose regular work is linked to music, either as performers (two patients) or instrument makers. RESULTS: The patients showed extensive cross-reactivity between the different Dalbergia woods. The two musicians exhibited symptoms exclusively in the contact areas, while the instrument makers showed a pattern of airborne symptoms. The period from sensitisation to the development of symptoms varied greatly among the patients. CONCLUSIONS: The symptoms of allergic contact dermatitis to Dalbergia woods differ markedly depending on the route of contact. Cross-reactivity between the woods of this genus is very wide. The sensitising potential varies between the various Dalbergia woods, which require different contact periods depending on their sensitising power.
RESUMEN
Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral , Leucoencefalopatías , Enfermedades Neurodegenerativas , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Mutación , Factor 2B Eucariótico de Iniciación/genética , Factor 2B Eucariótico de Iniciación/metabolismo , Encéfalo/metabolismo , Leucoencefalopatías/metabolismoRESUMEN
BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD. METHODS: Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 study (DNLI-C-0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI-C-0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers. RESULTS: A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment-emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was ~1 (range, 0.7-1.8). Dose-dependent median reductions from baseline were observed in whole-blood phosphorylated serine 935 LRRK2 (≤98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤93%), cerebrospinal fluid total LRRK2 (≤50%), and urine bis (monoacylglycerol) phosphate (≤74%). CONCLUSIONS: At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. © 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Leucocitos Mononucleares/metabolismo , Voluntarios Sanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Biomarcadores/metabolismo , MutaciónRESUMEN
Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (14), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis.
Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Leucina Zippers , Quinasas Quinasa Quinasa PAM , Sistema Nervioso Central/metabolismo , Encéfalo/metabolismo , Enfermedades Neurodegenerativas/metabolismoRESUMEN
BACKGROUND: Iodinated contrast media produce non-immediate hypersensitivity reactions (NIHR). The goal of this prospective study was to determine the utility of skin tests and the subsequent tolerance to negative skin-tested iodinated contrasts in patients with NIHR caused by iomeprol. METHODS: Prick and intradermal tests with iomeprol, iopamidol, iopromide, and iobitridol were performed in all patients. IV challenge with the causative contrast (iomeprol in 90%) was made if skin tests were negative. In case of a positive skin test with the causal contrast, or a positive challenge test with it, IV challenge test with an alternative, negative skin-tested contrast was performed in all patients. RESULTS: Skin tests were positive in 47.6% (20/42) of patients with NIHR induced by iomeprol. Of the 66 challenge tests performed with negative skin-tested iodinated contrasts, tolerance was confirmed in 35 (53%): 32 iomeron, 2 iobitridol, 1 iopamidol. Cross-reactivity between iomeprol and iopamidol was 22% (4/20 in patients with positive skin tests and 5/21 in patients with negative skin tests). CONCLUSIONS: Sensitivity of the skin tests was less than 50% NIHRs due to iomeprol, while the negative predictive value of skin tests in patients who tolerated challenges with alternative contrasts (mainly iopamidol) was 53% (35 tolerated out of 66 performed). The cross-reactivity between iomeprol and iopamidol is high.
Asunto(s)
Hipersensibilidad Inmediata , Compuestos de Yodo , Humanos , Yopamidol/efectos adversos , Medios de Contraste/efectos adversos , Estudios Prospectivos , Pruebas Cutáneas , Compuestos de Yodo/efectos adversos , Hipersensibilidad Inmediata/diagnóstico , Hipersensibilidad Inmediata/etiologíaRESUMEN
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for Parkinson's disease (PD). Increased LRRK2 kinase activity is thought to impair lysosomal function and may contribute to the pathogenesis of PD. Thus, inhibition of LRRK2 is a potential disease-modifying therapeutic strategy for PD. DNL201 is an investigational, first-in-class, CNS-penetrant, selective, ATP-competitive, small-molecule LRRK2 kinase inhibitor. In preclinical models, DNL201 inhibited LRRK2 kinase activity as evidenced by reduced phosphorylation of both LRRK2 at serine-935 (pS935) and Rab10 at threonine-73 (pT73), a direct substrate of LRRK2. Inhibition of LRRK2 by DNL201 demonstrated improved lysosomal function in cellular models of disease, including primary mouse astrocytes and fibroblasts from patients with Gaucher disease. Chronic administration of DNL201 to cynomolgus macaques at pharmacologically relevant doses was not associated with adverse findings. In phase 1 and phase 1b clinical trials in 122 healthy volunteers and in 28 patients with PD, respectively, DNL201 at single and multiple doses inhibited LRRK2 and was well tolerated at doses demonstrating LRRK2 pathway engagement and alteration of downstream lysosomal biomarkers. Robust cerebrospinal fluid penetration of DNL201 was observed in both healthy volunteers and patients with PD. These data support the hypothesis that LRRK2 inhibition has the potential to correct lysosomal dysfunction in patients with PD at doses that are generally safe and well tolerated, warranting further clinical development of LRRK2 inhibitors as a therapeutic modality for PD.
Asunto(s)
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Animales , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Lisosomas/metabolismo , Ratones , Mutación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , FosforilaciónAsunto(s)
Acrilatos/efectos adversos , Dermatitis Alérgica por Contacto/etiología , Geles/efectos adversos , Ultrasonografía , Urea/análogos & derivados , Acrilatos/análisis , Adulto , Dermatitis Alérgica por Contacto/diagnóstico , Emulsionantes/efectos adversos , Emulsionantes/análisis , Femenino , Geles/química , Humanos , Masculino , Persona de Mediana Edad , Pruebas del Parche , Conservadores Farmacéuticos/efectos adversos , Conservadores Farmacéuticos/análisis , Urea/efectos adversos , Urea/análisisRESUMEN
BACKGROUND: Fixed drug eruption (FDE) is a characteristic form of intraepidermal CD8+ T cell-mediated drug reaction, with repeated appearance of isolated or multiple skin lesions in the same location after receiving the offending drug. Non-steroidal anti-inflammatory drugs (NSAID) are the most common cause. Selective inhibitors of inducible cyclooxygenase 2 (COX-2) provoke a lesser degree of allergic or idiosyncratic adverse reactions than conventional NSAID, but they can cause skin reactions of variable severity. OBJECTIVE: Etoricoxib has been related to a variety of unusual skin reactions, including several reports of FDE. METHODS: We perfomed epicutaneous test to diagnose patients with suspected etoricoxib fixe drug rash due to clinical features and reproducibility on at least two occasions. RESULTS: We present seven new cases of etoricoxib-induced fixed drug eruption, with a diagnosis based on clinical presentation. This diagnosis was confirmed by an etoricoxib-positive lesional patch test in six cases and by a positive low-dose oral challenge in the other one. Two patients showed negative patch tests with celecoxib (10% in pet.) on the residual lesions, and oral tolerance was confirmed in one. CONCLUSION: To our knowledge, this is the largest series on FDE induced by etoricoxib reported to date.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Dermatitis Alérgica por Contacto/etiología , Erupciones por Medicamentos/etiología , Etoricoxib/efectos adversos , Adulto , Anciano , Dermatitis Alérgica por Contacto/diagnóstico , Erupciones por Medicamentos/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas del ParcheRESUMEN
BACKGROUND: COVID-19 cutaneous manifestations have been recently described and classified in five different clinical patterns, including acral erythema-edema (pseudo-chilblain), maculopapular exanthemas, vesicular eruptions, urticarial lesions, and livedo or necrosis. OBJECTIVES: The objective of this study was to examine the skin of hospitalized patients with a confirmed diagnosis of COVID-19 disease and describe the real prevalence of skin manifestations. METHODS: A cross-sectional study, which included hospitalized patients in Cruces University Hospital from April 14-30, 2020, with a laboratory-confirmed diagnosis of COVID-19 (with polymerase chain reaction and/or serology tests), was conducted. Entire body surface examination was performed by experienced dermatologists to search for cutaneous manifestations related to COVID-19 disease. RESULTS: From a sample of 75 patients, 14 (18.7%) developed cutaneous manifestations possibly related to COVID-19. We found six patients with acral erythema-edema (pseudo-chilblain) (42.8%), four patients with maculopapular exanthemas (28.6%), two patients with urticarial lesions (14.3%), one patient with livedo reticularis-like lesions (7.15%), and one patient with vesicular eruption (7.15%). CONCLUSIONS: Our study provides a more plausible relationship between the main cutaneous patterns and COVID-19 in hospitalized patients as all of them had a confirmatory laboratory test. Skin manifestations are frequent but mild with spontaneous resolution. These findings are nonspecific and can be similar to other viral infections and adverse drug reactions in hospitalized patients.
Asunto(s)
COVID-19/complicaciones , Edema/virología , Enfermedades de la Piel/virología , Anciano , Vesícula/virología , Estudios Transversales , Eritema/virología , Exantema/virología , Femenino , Hospitalización , Humanos , Livedo Reticularis/virología , Masculino , Persona de Mediana Edad , SARS-CoV-2 , Centros de Atención Terciaria , Urticaria/virologíaRESUMEN
Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.
Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Fluoroquinolonas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Inhibidores de Topoisomerasa II/farmacología , Antibacterianos/síntesis química , Antibacterianos/metabolismo , Antibacterianos/toxicidad , Sitios de Unión , Línea Celular Tumoral , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Topoisomerasa de ADN IV/química , Fluoroquinolonas/síntesis química , Fluoroquinolonas/metabolismo , Fluoroquinolonas/toxicidad , Bacterias Gramnegativas/enzimología , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/metabolismo , Inhibidores de Topoisomerasa II/toxicidadRESUMEN
LpxD, acyl-ACP-dependent N-acyltransferase, is the third enzyme of lipid A biosynthesis in Gram-negative bacteria. A recent probe-based screen identified several compounds, including 6359-0284 (compound 1), that inhibit the enzymatic activity of Escherichia coli (E. coli) LpxD. Here, we use these inhibitors to chemically validate LpxD as an attractive antibacterial target. We first found that compound 1 was oxidized in solution to the more stable aromatized tetrahydro-pyrazolo-quinolinone compound 1o. From the Escherichia coli strain deficient in efflux, we isolated a mutant that was less susceptible to compound 1o and had an lpxD missense mutation (Gly268Cys), supporting the cellular on-target activity. Using surface plasma resonance, we showed direct binding to E. coli LpxD for compound 1o and other reported LpxD inhibitors in vitro. Furthermore, we determined eight cocrystal structures of E. coli LpxD/inhibitor complexes. These costructures pinpointed the 4'-phosphopantetheine binding site as the common ligand binding hotspot, where hydrogen bonds to Gly269 and/or Gly287 were important for inhibitor binding. In addition, the LpxD/compound 1o costructure rationalized the reduced activity of compound 1o in the LpxDGly268Cys mutant. Moreover, we obtained the LpxD structure in complex with a previously reported LpxA/LpxD dual targeting peptide inhibitor, RJPXD33, providing structural rationale for the unique dual targeting properties of this peptide. Given that the active site residues of LpxD are conserved in multidrug resistant Enterobacteriaceae, this work paves the way for future LpxD drug discovery efforts combating these Gram-negative pathogens.
Asunto(s)
Aciltransferasas , Proteínas de Escherichia coli , Escherichia coli , Aciltransferasas/antagonistas & inhibidores , Aciltransferasas/genética , Sitios de Unión , Escherichia coli/enzimología , Escherichia coli/genética , Proteínas de Escherichia coli/antagonistas & inhibidores , Lípido A , LipopolisacáridosRESUMEN
Searching for high-performance permanent magnets components with no limitation in shape and dimensions is highly desired to overcome the present design and manufacturing restrictions, which affect the efficiency of the final devices in energy, automotive and aerospace sectors. Advanced 3D-printing of composite materials and related technologies is an incipient route to achieve functional structures avoiding the limitations of traditional manufacturing. Gas-atomized MnAlC particles combined with polymer have been used in this work for fabricating scalable rare earth-free permanent magnet composites and extruded flexible filaments with continuous length exceeding 10 m. Solution casting has been used to synthesize homogeneous composites with tuned particles content, made of a polyethylene (PE) matrix embedding quasi-spherical particles of the ferromagnetic τ-MnAlC phase. A maximum filling factor of 86.5 and 72.3% has been obtained for the composite and the filament after extrusion, respectively. The magnetic measurements reveal no deterioration of the properties of the MnAlC particles after the composite synthesis and filament extrusion. The produced MnAlC/PE materials will serve as precursors for an efficient and scalable design and fabrication of end-products by different processing techniques (polymerized cold-compacted magnets and 3D-printing, respectively) in view of technological applications (from micro electromechanical systems to energy and transport applications).
RESUMEN
The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli Δ tolC mutant strain.
Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas de Escherichia coli/antagonistas & inhibidores , Compuestos Heterocíclicos con 2 Anillos/farmacología , Nucleotidiltransferasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/metabolismo , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/metabolismo , Bencimidazoles/farmacología , Sitios de Unión , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nucleotidiltransferasas/química , Nucleotidiltransferasas/metabolismo , Unión Proteica , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacología , Triazoles/síntesis química , Triazoles/química , Triazoles/metabolismo , Triazoles/farmacologíaRESUMEN
In the preceding manuscript [ Moreau et al. 2018 , 10.1021/acs.jmedchem.7b01691 ] we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.
Asunto(s)
Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas de Escherichia coli/antagonistas & inhibidores , Compuestos Heterocíclicos con 2 Anillos/farmacología , Nucleotidiltransferasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/metabolismo , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/metabolismo , Bencimidazoles/farmacología , Sitios de Unión , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mutación , Nucleotidiltransferasas/química , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Unión Proteica , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacología , Triazoles/síntesis química , Triazoles/química , Triazoles/metabolismo , Triazoles/farmacologíaRESUMEN
Drug-resistant Gram-negative bacteria are of increasing concern worldwide. Novel antibiotics are needed, but their development is complicated by the requirement to simultaneously optimize molecules for target affinity and cellular potency, which can result in divergent structure-activity relationships (SARs). These challenges were exemplified during our attempts to optimize inhibitors of the bacterial enzyme CoaD originally identified through a biochemical screen. To facilitate lead optimization, we developed mass spectroscopy assays based on the hypothesis that levels of CoA metabolites would reflect the cellular enzymatic activity of CoaD. Using these methods, we were able to monitor the effects of cellular enzyme inhibition at compound concentrations up to 100-fold below the minimum inhibitory concentration (MIC), a common metric of growth inhibition. Furthermore, we generated a panel of efflux pump mutants to dissect the susceptibility of a representative CoaD inhibitor to efflux. These approaches allowed for a nuanced understanding of the permeability and efflux liabilities of the series and helped guide optimization efforts to achieve measurable MICs against wild-type E. coli.
Asunto(s)
Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Metabolómica/métodos , Nucleotidiltransferasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
Tankyrase activity has been linked to the regulation of intracellular axin levels, which have been shown to be crucial for the Wnt pathway. Deregulated Wnt signaling is important for the genesis of many diseases including cancer. We describe herein the discovery and development of a new series of tankyrase inhibitors. These pyranopyridones are highly active in various cell-based assays. A fragment/structure based optimization strategy led to a compound with good pharmacokinetic properties that is suitable for in vivo studies and further development.
RESUMEN
The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/química , Pirroles/química , Diseño de Fármacos , Humanos , Janus Quinasa 3/metabolismo , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Fosforilación , Piperidinas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Quinolinas/farmacología , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacocinética , Perros , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Hepacivirus/enzimología , Humanos , Modelos Moleculares , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition that has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics, and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.