RESUMEN
The isomers of dibenzylamino-1-methylcyclohexan-1-ol and dibenzylamino-1-trifluoromethylcyclohexan-1-ol have been prepared. The stereochemistry of these compounds was unequivocally assigned through a combination of NMR spectroscopy and single crystal X-ray analysis. The cis-isomer of 3-N,N-dibenzylamino-1-trifluoromethylcyclohexanol and its derivatives display an unusual conformational behaviour in both solution-phase and the solid-state, where the amino group usually adopts an axial conformation.
Asunto(s)
Bencilaminas/síntesis química , Ciclohexanoles/síntesis química , Bencilaminas/química , Cristalografía por Rayos X , Ciclohexanoles/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identified that are not apparent when using conventional, context-independent approaches.
Asunto(s)
Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Algoritmos , Bases de Datos Factuales , Canales de Potasio Éter-A-Go-Go/química , Humanos , Ligandos , Lípidos/química , Estructura Molecular , SolubilidadRESUMEN
Machine learning approaches promise to accelerate and improve success rates in medicinal chemistry programs by more effectively leveraging available data to guide a molecular design. A key step of an automated computational design algorithm is molecule generation, where the machine is required to design high-quality, drug-like molecules within the appropriate chemical space. Many algorithms have been proposed for molecular generation; however, a challenge is how to assess the validity of the resulting molecules. Here, we report three Turing-inspired tests designed to evaluate the performance of molecular generators. Profound differences were observed between the performance of molecule generators in these tests, highlighting the importance of selection of the appropriate design algorithms for specific circumstances. One molecule generator, based on match molecular pairs, performed excellently against all tests and thus provides a valuable component for machine-driven medicinal chemistry design workflows.
Asunto(s)
Algoritmos , Aprendizaje Automático , Química Farmacéutica , Diseño de Fármacos , Humanos , Estructura MolecularRESUMEN
The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
Asunto(s)
Ensayos Analíticos de Alto Rendimiento/métodos , Proteínas/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Quimiocina CCL2/biosíntesis , Cristalografía por Rayos X , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inhibidores , Leucocitos/efectos de los fármacos , Masculino , Ratones , Modelos Moleculares , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Bibliotecas de Moléculas PequeñasRESUMEN
Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.
Asunto(s)
Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Quinolinas/administración & dosificación , Quinolinas/química , Administración Oral , Animales , Bovinos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Masculino , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.
Asunto(s)
Química Farmacéutica/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Inhibidores de Fosfodiesterasa 4 , Pirazoles/síntesis química , Pirazoles/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Benzamidas/farmacología , Cristalografía por Rayos X/métodos , Ciclopropanos/farmacología , Diseño de Fármacos , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Modelos Biológicos , Modelos Químicos , Pirrolidinonas/química , Ratas , Rolipram/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Relación Estructura-Actividad , Administración por Inhalación , Animales , Fosfatidilinositol 3-Quinasa Clase Ia/química , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Enlace de Hidrógeno , Isoquinolinas/química , Células de Riñón Canino Madin Darby , RatasRESUMEN
A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Enfermedades Respiratorias/tratamiento farmacológico , Administración por Inhalación , Animales , Disponibilidad Biológica , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Sprague-Dawley , Enfermedades Respiratorias/metabolismo , Relación Estructura-ActividadRESUMEN
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
Asunto(s)
Indazoles/química , Oxazoles/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Enfermedades Respiratorias/tratamiento farmacológico , Sulfonamidas/química , Administración por Inhalación , Animales , Asma/tratamiento farmacológico , Femenino , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Indoles , Isoenzimas/antagonistas & inhibidores , Masculino , Microsomas/metabolismo , Simulación del Acoplamiento Molecular , Ovalbúmina/inmunología , Oxazoles/farmacocinética , Oxazoles/farmacología , Piperazinas , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Conejos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Células Th2/inmunologíaRESUMEN
In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.
Asunto(s)
Química Farmacéutica/educación , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Curriculum , Industria Farmacéutica/métodos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Modelos Moleculares , Inhibidores de las Quinasa Fosfoinosítidos-3 , SolubilidadRESUMEN
REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.
Asunto(s)
Aminas/síntesis química , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/agonistas , Aminas/química , Aminas/farmacología , Animales , Disponibilidad Biológica , Proteínas Portadoras/metabolismo , Línea Celular , Ritmo Circadiano , Glicina/análogos & derivados , Glicina/síntesis química , Glicina/química , Glicina/farmacología , Humanos , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Receptores Nucleares Huérfanos/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas de Unión al ARN , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
Triphenylphosphine tagged with a short poly-(ethyleneglycol)-ω-monomethyl ether chain (light MPEG, 10−16 ethylenoxy units, (M)TPP-G2) and an MPEG-tagged version of diethyl azodicarboxylate ((M)DEAD) have been used to prepare a 20 member library of esters, ethers, and sulfonamides, with cLogP's in the range of 1.4−5.7 on a 0.1 mmol scale. Removal of MPEG-tagged side products was achieved by MPEG-assisted solid-phase extraction (MSPE) on prepacked silica columns to give the products in good yield and high purity.
Asunto(s)
Técnicas Químicas Combinatorias , Peso Molecular , Extracción en Fase SólidaRESUMEN
Neighborhood behavior describes the extent to which small structural changes defined by a molecular descriptor are likely to lead to small property changes. This study evaluates two methods for the quantification of neighborhood behavior: the optimal diagonal method of Patterson et al. and the optimality criterion method of Horvath and Jeandenans. The methods are evaluated using twelve different types of fingerprint (both 2D and 3D) with screening data derived from several lead optimization projects at GlaxoSmithKline. The principal focus of the work is the design of chemical arrays during lead optimization, and the study hence considers not only biological activity but also important drug properties such as metabolic stability, permeability, and lipophilicity. Evidence is provided to suggest that the optimality criterion method may provide a better quantitative description of neighborhood behavior than the optimal diagonal method.
Asunto(s)
Diseño de Fármacos , PermeabilidadRESUMEN
2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.