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1.
J Biomol Screen ; 14(5): 476-84, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19483144

RESUMEN

Preserving the integrity of the compound collection and providing high-quality materials for drug discovery in an efficient and cost-effective manner are 2 major challenges faced by compound management (CM) at Bristol-Myers Squibb (BMS). The demands on CM include delivering hundreds of thousands of compounds a year to a variety of operations. These operations range from single-compound requests to hit identification support and just-in-time assay plate provision for lead optimization. Support needs for these processes consist of the ability to rapidly provide compounds as solids or solutions in a variety of formats, establishing proper long- and short-term storage conditions and creating appropriate methods for handling concentrated, potent compounds for delivery to sensitive biological assays. A series of experiments evaluating the effects of processing compounds with volatile solvents, storage conditions that can induce freeze/thaw cycles, and the delivery of compounds were performed. This article presents the results of these experiments and how they affect compound integrity and the accuracy of compound management processes.


Asunto(s)
Bioensayo , Descubrimiento de Drogas , Estabilidad de Medicamentos , Bioensayo/instrumentación , Bioensayo/métodos , Bioensayo/normas , Descubrimiento de Drogas/instrumentación , Descubrimiento de Drogas/métodos , Preparaciones Farmacéuticas/química , Reproducibilidad de los Resultados
2.
Drug Discov Today ; 13(1-2): 44-51, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18190863

RESUMEN

We review strategic approaches taken over an eight-year period at BMS to implement new high-throughput approaches to lead discovery. Investments in compound management infrastructure and chemistry library production capability allowed significant growth in the size, diversity and quality of the BMS compound collection. Screening platforms were upgraded with robust automated technology to support miniaturized assay formats, while workflows and information handling technologies were streamlined for improved performance. These technology changes drove the need for a supporting organization in which critical engineering, informatics and scientific skills were more strongly represented. Taken together, these investments led to significant improvements in speed and productivity as well a greater impact of screening campaigns on the initiation of new drug discovery programs.


Asunto(s)
Diseño de Fármacos , Industria Farmacéutica/economía , Tecnología Farmacéutica/métodos , Gastos de Capital , Inversiones en Salud , Sector Privado , Tecnología Farmacéutica/economía
3.
J Biomol Screen ; 19(4): 595-605, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24241710

RESUMEN

Recent genetic evidence suggests that the diacylglycerol lipase (DAGL-α) isoform is the major biosynthetic enzyme for the most abundant endocannabinoid, 2-arachidonoyl-glycerol (2-AG), in the central nervous system. Revelation of its essential role in regulating retrograde synaptic plasticity and adult neurogenesis has made it an attractive therapeutic target. Therefore, it has become apparent that selective inhibition of DAGL-α enzyme activity with a small molecule could be a strategy for the development of novel therapies for the treatment of disease indications such as depression, anxiety, pain, and cognition. In this report, the authors present the identification of small-molecule inhibitor chemotypes of DAGL-α, which were selective (≥10-fold) against two other lipases, pancreatic lipase and monoacylglycerol lipase, via high-throughput screening of a diverse compound collection. Seven chemotypes of interest from a list of 185 structural clusters, which included 132 singletons, were initially selected for evaluation and characterization. Selection was based on potency, selectivity, and chemical tractability. One of the chemotypes, the glycine sulfonamide series, was prioritized as an initial lead for further medicinal chemistry optimization.


Asunto(s)
Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Lipoproteína Lipasa/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas , Línea Celular , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Cinética , Lipoproteína Lipasa/metabolismo , Reproducibilidad de los Resultados , Especificidad por Sustrato
4.
J Biomol Screen ; 16(5): 476-85, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21406618

RESUMEN

Protein tyrosine phosphatase-γ (PTP-γ) is a receptor-like PTP whose biological function is poorly understood. A recent mouse PTP-γ genetic deletion model associated the loss of PTP-γ gene expression with a potential antidepressant phenotype. This led the authors to screen a subset of the Bristol-Myers Squibb (BMS) compound collection to identify selective small-molecule inhibitors of receptor-like PTP-γ (RPTP-γ) for use in evaluating enzyme function in vivo. Here, they report the design of a high-throughput fluorescence resonance energy transfer (FRET) assay based on the Z'-LYTE technology to screen for inhibitors of RPTP-γ. A subset of the BMS diverse compound collection was screened and several compounds identified as RPTP-γ inhibitors in the assay. After chemical triage and clustering, compounds were assessed for potency and selectivity by IC(50) determination with RPTP-γ and two other phosphatases, PTP-1B and CD45. One hundred twenty-nine RPTP-γ selective (defined as IC(50) value greater than 5- to 10-fold over PTP-1B and CD45) inhibitors were identified and prioritized for evaluation. One of these hits, 3-(3, 4-dichlorobenzylthio) thiophene-2-carboxylic acid, was the primary chemotype for the initiation of a medicinal chemistry program.


Asunto(s)
Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/metabolismo , Ensayos Analíticos de Alto Rendimiento , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/antagonistas & inhibidores , Dimetilsulfóxido/farmacología , Inhibidores Enzimáticos/química , Estabilidad de Enzimas/efectos de los fármacos , Reproducibilidad de los Resultados , Proyectos de Investigación , Sensibilidad y Especificidad , Solventes/farmacología
5.
Nat Rev Drug Discov ; 10(3): 188-95, 2011 03.
Artículo en Inglés | MEDLINE | ID: mdl-21358738

RESUMEN

High-throughput screening (HTS) has been postulated in several quarters to be a contributory factor to the decline in productivity in the pharmaceutical industry. Moreover, it has been blamed for stifling the creativity that drug discovery demands. In this article, we aim to dispel these myths and present the case for the use of HTS as part of a proven scientific tool kit, the wider use of which is essential for the discovery of new chemotypes.


Asunto(s)
Investigación Biomédica , Evaluación Preclínica de Medicamentos , Animales , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/normas , Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Humanos , Bibliotecas de Moléculas Pequeñas
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