RESUMEN
Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options1. No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years1. Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB2FGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB2FGC as a tractable target for antimicrobial drug development.
Asunto(s)
Antibacterianos , Lipopolisacáridos , Proteínas de Transporte de Membrana , Animales , Humanos , Ratones , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/metabolismo , Antibacterianos/clasificación , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Lipopolisacáridos/metabolismo , Pruebas de Sensibilidad Microbiana , Proteínas de Transporte de Membrana/metabolismo , Transporte Biológico/efectos de los fármacos , Modelos Animales de Enfermedad , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Desarrollo de MedicamentosRESUMEN
Drug discovery is a multifaceted endeavor encompassing as its core element the generation of structure-activity relationship (SAR) data by repeated chemical synthesis and biological testing of tailored molecules. Herein, we report on the development of a flow-based biochemical assay and its seamless integration into a fully automated system comprising flow chemical synthesis, purification and in-line quantification of compound concentration. This novel synthesis-screening platform enables to obtain SAR data on b-secretase (BACE1) inhibitors at an unprecedented cycle time of only 1 h instead of several days. Full integration and automation of industrial processes have always led to productivity gains and cost reductions, and this work demonstrates how applying these concepts to SAR generation may lead to a more efficient drug discovery process.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Automatización , Evaluación Preclínica de Medicamentos , Humanos , Técnicas Analíticas Microfluídicas/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Inhibidores de Proteasas/metabolismo , Unión Proteica , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Relación Estructura-ActividadRESUMEN
The development of a stereoselective total synthesis of ß-dihydroagarofuran 4 is described. This compound contains the same oxygenation pattern on its 'lower-rim' as found in the natural sesquiterpene (-)-euonyminol (1) and it is expected that the route described should be applicable to the synthesis of that complex natural product. (-)-Euonyminol is found as the core scaffold of a series of complex macrodilactone sesquiterpenoids isolated from the Celastraceae which possess interesting biological activities (e.g. anti-HIV activity). The synthetic route builds upon an epoxidative asymmetric desymmetrisation of meso-diallylic alcohol 10 that we have reported previously. It features a lactate Ireland-Claisen rearrangement to establish the quaternary stereocentre at C11 (27â28a) and an unusual dealkylative intramolecular epoxide-opening by the C11 methyl ether to establish the tetrahydrofuranyl C-ring of the ß-dihydroagarofuran skeleton (35â36).
Asunto(s)
Modelos Químicos , Sesquiterpenos/química , Sesquiterpenos/síntesis química , Técnicas de Química Sintética , Furanos/química , Oxígeno/química , Propanoles/química , Estereoisomerismo , Especificidad por SustratoRESUMEN
The optimisation of affinity and selectivity in a novel series of dual 5-HT5A/5-HT7 receptor ligands is described. Brain penetrant 2-aminodihydroquinazolines with low nanomolar affinities were identified.
Asunto(s)
Guanidinas/metabolismo , Quinazolinas/metabolismo , Receptores de Serotonina/metabolismo , Encéfalo/metabolismo , Guanidinas/química , Guanidinas/farmacocinética , Guanidinas/farmacología , Humanos , Cinética , Ligandos , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Receptores de Serotonina/química , Relación Estructura-ActividadRESUMEN
The optimisation of molecular properties within a series of 2-amino dihydroquinazoline 5-HT5A/5-HT7 receptor ligands resulted in a significantly improved brain-to-plasma ratio, enhancing the pharmacological utility of these compounds. By modulating the lipophilicity and pKa, a 20-fold increase in brain-to-plasma ratio could be achieved, leading to micromolar brain concentrations after oral administration. The enantiomers of one representative of this series of improved compounds were separated, and the configuration of the eutomer was determined by X-ray crystallography.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Guanidinas/farmacocinética , Receptores de Serotonina/metabolismo , Animales , Guanidinas/química , Guanidinas/farmacología , Humanos , Cinética , Ligandos , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Ratas , Receptores de Serotonina/química , Relación Estructura-ActividadRESUMEN
A series of 1,3-dihydrobenzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists. Attachment of an 8-(2-aryl)-ethynyl-moiety produced compounds inhibiting the binding of [(3)H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and mGluR3.
Asunto(s)
Azepinas/síntesis química , Azepinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Azepinas/química , Células CHO , Cricetinae , Cricetulus , Estructura Molecular , RatasRESUMEN
The identification of small-molecule modulators of protein function, and the process of transforming these into high-content lead series, are key activities in modern drug discovery. The decisions taken during this process have far-reaching consequences for success later in lead optimization and even more crucially in clinical development. Recently, there has been an increased focus on these activities due to escalating downstream costs resulting from high clinical failure rates. In addition, the vast emerging opportunities from efforts in functional genomics and proteomics demands a departure from the linear process of identification, evaluation and refinement activities towards a more integrated parallel process. This calls for flexible, fast and cost-effective strategies to meet the demands of producing high-content lead series with improved prospects for clinical success.
Asunto(s)
Diseño de Fármacos , Secuencias de Aminoácidos , Técnicas Químicas Combinatorias , Evaluación Preclínica de Medicamentos , Genómica , ProteómicaRESUMEN
Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular polyketide synthase multienzymes by an assembly-line process in which each module of enzymes in turn specifies attachment of a particular chemical unit. Although polyketide synthase encoding genes have been successfully engineered to produce novel analogues, the process can be relatively slow, inefficient, and frequently low-yielding. We now describe a method for rapidly recombining polyketide synthase gene clusters to replace, add or remove modules that, with high frequency, generates diverse and highly productive assembly lines. The method is exemplified in the rapamycin biosynthetic gene cluster where, in a single experiment, multiple strains were isolated producing new members of a rapamycin-related family of polyketides. The process mimics, but significantly accelerates, a plausible mechanism of natural evolution for modular polyketide synthases. Detailed sequence analysis of the recombinant genes provides unique insight into the design principles for constructing useful synthetic assembly-line multienzymes.
Asunto(s)
Vías Biosintéticas/genética , Evolución Molecular , Variación Genética , Familia de Multigenes , Bioingeniería , Sintasas Poliquetidas/genética , Sirolimus/química , Sirolimus/metabolismoRESUMEN
A computer-based method was developed for rapid and automatic identification of potential "frequent hitters". These compounds show up as hits in many different biological assays covering a wide range of targets. A scoring scheme was elaborated from substructure analysis, multivariate linear and nonlinear statistical methods applied to several sets of one and two-dimensional molecular descriptors. The final model is based on a three-layered neural network, yielding a predictive Matthews correlation coefficient of 0.81. This system was able to correctly classify 90% of the test set molecules in a 10-times cross-validation study. The method was applied to database filtering, yielding between 8% (compilation of trade drugs) and 35% (Available Chemicals Directory) potential frequent hitters. This filter will be a valuable tool for the prioritization of compounds from large databases, for compound purchase and biological testing, and for building new virtual libraries.
Asunto(s)
Bases de Datos Factuales , Compuestos Orgánicos/química , Modelos Lineales , Estructura Molecular , Redes Neurales de la Computación , Dinámicas no Lineales , Preparaciones Farmacéuticas/químicaRESUMEN
Improving on the poor success rates in the drug discovery industry requires that knowledge-based decisions are made to advance or stop a lead candidate as early as possible in the discovery process. Failure to make such timely decisions on the rigorous selection of lead candidates has costly time and resource implications in downstream drug development. To meet this challenge dedicated 'hit to lead' groups have recently been established in many major pharmaceutical companies, and a key to the success of such groups is establishing a clear consistent process and rigorous metrics for lead quality. The importance of such a "Lead Generation" group within the drug discovery process will be highlighted with the aim of placing a greater level of emphasis in discovering and refining novel lead series with enhanced drug-like properties. This activity is facilitated by the application of productivity enhancing, integrated technologies coupled with the early evaluation of drug-like properties in the lead refinement process to ensure that a balanced activity - properties profile can be attained before committing to a full lead optimisation program. This article will survey the processes and tools employed in the hit to lead process in such a "Lead Generation" group in order to achieve these objectives, emphasising the possible gains in productivity through close, early interactions between chemistry and other expert groups.
Asunto(s)
Química Farmacéutica/tendencias , Preparaciones Farmacéuticas/química , Proyectos de Investigación , Tecnología Farmacéutica/tendencias , Técnicas Químicas Combinatorias , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Industria Farmacéutica , Eficiencia , Relación Estructura-ActividadRESUMEN
The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.
Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Piperazinas/síntesis química , Psicotrópicos/síntesis química , Esquizofrenia/tratamiento farmacológico , Sulfonas/síntesis química , Animales , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Macaca fascicularis , Masculino , Ratones , Microdiálisis , Actividad Motora/efectos de los fármacos , Técnicas de Placa-Clamp , Piperazinas/farmacocinética , Piperazinas/farmacología , Psicotrópicos/farmacocinética , Psicotrópicos/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Sulfonas/farmacocinética , Sulfonas/farmacologíaRESUMEN
A computer-based method has been developed for prediction of the hERG (human ether-à-go-go related gene) K(+)-channel affinity of low molecular weight compounds. hERG channel blockage is a major concern in drug design, as such blocking agents can cause sudden cardiac death. Various techniques were applied to finding appropriate molecular descriptors for modeling structure-activity relationships: substructure analysis, self-organizing maps (SOM), principal component analysis (PCA), partial least squares fitting (PLS), and supervised neural networks. The most accurate prediction system was based on an artificial neural network. In a validation study, 93 % of the nonblocking agents and 71 % of the hERG channel blockers were correctly classified. This virtual screening method can be used for general compound-library shaping and combinatorial library design.
Asunto(s)
Proteínas de Transporte de Catión , Proteínas de Unión al ADN , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/química , Transactivadores , Técnicas Químicas Combinatorias , Bases de Datos Factuales , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go , Humanos , Modelos Lineales , Estructura Molecular , Redes Neurales de la Computación , Dinámicas no Lineales , Relación Estructura-Actividad , Regulador Transcripcional ERGRESUMEN
The synthesis and in vitro structure-activity relationships (SAR) of a series of triazoles as A(2A) receptor antagonists is reported. This resulted in the identification of potent, selective and permeable 1,2,4-triazoles such as 42 for further optimization and evaluation in vivo.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Membrana Celular/química , Triazoles/síntesis química , Triazoles/farmacología , Animales , Técnicas In Vitro , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Screening of the Roche compound library led to the identification of 4-aminoquinoline 4 as structurally novel NR1/2B subtype selective NMDA receptor antagonist. The SAR which was developed in this series resulted in the discovery of highly potent and in vivo active blockers.
Asunto(s)
Aminoquinolinas/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Aminoquinolinas/química , Antagonistas de Aminoácidos Excitadores/química , Relación Estructura-ActividadRESUMEN
Screening of the Roche compound depository led to the identification of (1-benzyloxy-4,5-dihydro-1H-imidazol-2-yl)-butyl amine 4, a structurally novel NR1/2B subtype selective NMDA receptor antagonist. The structure-activity relationships developed in this series resulted in the discovery of a novel class of potent and selective NMDA receptor blockers displaying activity in vivo.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/química , Imidazoles/química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Células Cultivadas , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Imidazoles/administración & dosificación , Imidazoles/farmacología , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos DBA , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/fisiología , Convulsiones/prevención & controlRESUMEN
Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype selective NMDA receptor antagonists. We would now like to report our findings on structurally related pyridine analogues. The SAR developed in this series resulted in the discovery of high affinity antagonists which are selective (vs alpha1 and M1 receptors) and active in vivo.
Asunto(s)
Isoquinolinas/química , Isoquinolinas/farmacología , Piridinas/química , Piridinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Estimulación Acústica , Animales , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Concentración de Iones de Hidrógeno , Ratones , Ratones Endogámicos DBA , Convulsiones/etiología , Convulsiones/prevención & control , Relación Estructura-ActividadRESUMEN
A series of 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs alpha1 and M1 receptors) and activity in vivo.