RESUMEN
The relatively slow cycle time within medicinal chemistry from synthesis to assay is constantly being challenged to help improve the efficiency of the discovery process. While both synthesis and assay have been automated to varying degrees, there has, until recently, been limited focus on the complete design, make, and test process. This Innovations article outlines the development of Cyclofluidic from inception through to the commercialization of a fully integrated closed loop design, synthesis, and screen platform.
RESUMEN
The synthesis and structure-activity relationship of a novel series of aminopyrimidines are exemplified. Results of key compounds from within this series in the E-selectin reporter cell assay are also reported.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Pirimidinas/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Selectina E/metabolismo , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Moleculares , Piridinas/síntesis química , Piridinas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Imidazoles/química , Conformación Molecular , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Biológicos , Piridinas/síntesis química , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Amidas/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Piridinas/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.
Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Evaluación Preclínica de Medicamentos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Piridinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
[reaction: see text] A new method for the solid-phase synthesis of cyanamides is described. The attachment of a secondary amine to solid support is accomplished using Merrifield resin. After functionalization, cleavage is readily achieved with cyanogen bromide to afford the desired cyanamide.
Asunto(s)
Inhibidores de Cisteína Proteinasa/síntesis química , Nitrilos/síntesis química , Pirrolidinas/síntesis química , Catálisis , Bromuro de Cianógeno , Inhibidores de Cisteína Proteinasa/farmacología , Indicadores y ReactivosRESUMEN
A novel integrated discovery platform has been used to synthesize and biologically assay a series of xanthine-derived dipeptidyl peptidase 4 (DPP4) antagonists. Design, synthesis, purification, quantitation, dilution, and bioassay have all been fully integrated to allow continuous automated operation. The system has been validated against a set of known DPP4 inhibitors and shown to give excellent correlation between traditional medicinal chemistry generated biological data and platform data. Each iterative loop of synthesis through biological assay took two hours in total, demonstrating rapid iterative structure-activity relationship generation.
RESUMEN
Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure-activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC50 > 8 against Abl kinase--both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.
Asunto(s)
Descubrimiento de Drogas , Microfluídica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Algoritmos , Relación Estructura-ActividadRESUMEN
Small aromatic ring systems are of central importance in the development of novel synthetic protein ligands. Here we generate a complete list of 24,847 such ring systems. We call this list and associated annotations VEHICLe, which stands for virtual exploratory heterocyclic library. Searches of literature and compound databases, using this list as substructure queries, identified only 1701 as synthesized. Using a carefully validated machine learning approach, we were able to estimate that the number of unpublished, but synthetically tractable, VEHICLe rings could be over 3000. However, analysis also shows that the rate of publication of novel examples to be as low as 5-10 per year. With this work, we aim to provide fresh stimulus to creative organic chemists by highlighting a small set of apparently simple ring systems that are predicted to be tractable but are, to the best of our knowledge, unconquered.
Asunto(s)
Compuestos Heterocíclicos/química , Descubrimiento de Drogas/tendencias , Compuestos Heterocíclicos/síntesis química , Compuestos Orgánicos/síntesis química , Compuestos Orgánicos/química , Reproducibilidad de los Resultados , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
A solid-phase synthesis of substituted cyclic urea derivatives as potential heterocyclic library scaffolds is described. 2-Amino-3-nitropyridine is attached to Wang resin via a carbamate linkage. Reduction of the nitro group was achieved with SnCl(2).2H(2)O. Reductive alkylation with a range of substituted benzaldehydes followed by cyclative cleavage afforded a small library of 3-substituted imidazo[4,5-b]pyridine-2-ones in 33-45% yield and 59-88% purity. Subsequently, this methodology was applied to the synthesis of 3-substituted imidazo[4,5-f]quinolin-2-ones.
RESUMEN
A novel series of aminopyrimidine IKK2 inhibitors have been developed which show excellent in vitro inhibition of this enzyme and good selectivity over the IKK1 isoform. The relative potency and selectivity of these compounds has been rationalized using QSAR and structure-based modelling.