A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.
Technologies that enable rapid screening of diverse reaction conditions are of critical importance to methodology development and reaction optimization, especially when molecules of high complexity and scarcity are involved. The lackofageneral solid dispensing method for chemical reagents on micro-and nanomole scale prevents the full utilization of reaction screening technologies.W eherein report the development of at echnology in whichg lass beads coated with solid chemical reagents (ChemBeads) enable the delivery of nanomole quantities of solid chemical reagents efficiently.B y exploring the concept of preferred screening sets,the flexibility and generality of this technology for high-throughput reaction screening was validated.High-throughput reaction screening is at ool that enables the investigation of large numbers of reaction conditions in parallel for ap articular chemical transformation. Reaction screening is an essential component for any new synthetic methodology development and is often utilized in complex natural product total synthesis.Whenconducted in parallel, it has the potential to offer high speed and efficiency in identifying an ovel or optimal reaction condition. Importantly,itisideal to miniaturize the reaction scale so that only milligram quantities of high-value intermediates are consumed when running arrays of reaction conditions. [1] Historically,the advancement and broad impact of high-throughput reaction screening has been hindered by al ack of suitable technologies to effectively handle reaction miniaturization. Only in the last few years have transformative advancements in this field started to emerge.S eminal papers from Merck and Pfizer have demonstrated the use of bioassay equipment and flow instrumentation to enable nanomole scale reaction screening in ah igh-throughput fashion. [2] However, ac ritical field-wide challenge that has yet to be addressed is how to effectively dispense diverse solid chemical reagents on nanomole (submilligram) scale accurately and efficiently. [3] Our search for ar obotic platform capable of dispensing av ariety of solids reagents in small quantities (< 1mg) was unsuccessful. [4] Each reagent would require individualized protocol development for accurate robotic dispensing, making it unrealistic to have as ingle platform for all solids. [2b,3b] As ar esult, tedious manual weighing has been the only reliable method. With nanomole quantities of material, this becomes unfeasible.T hus,n anomole scale reaction screening relies almost exclusively on the use of stock solutions made from reagents which are soluble in the reaction solvent. [2,5] Ideally, any combination of reagents,i nitially soluble or not, need to be incorporated in as creening set in order to have an unbiased assessment of reactivity.I nl ight of this field-wide challenge,w ee ndeavored to develop au niversal method for dispensing solid chemical reagents on nanomole scale with accuracy and efficiencyi nt he context of high throughput reaction screening.During our research, we became awa...
The productivity of medicinal chemistry programs can be significantly increased through the introduction of automation, leading to shortened discovery cycle times. Herein, we describe a platform that consolidates synthesis, purification, quantitation, dissolution, and testing of small molecule libraries. The system was validated through the synthesis and testing of two libraries of binders of polycomb protein EED, and excellent correlation of obtained data with results generated through conventional approaches was observed. The fully automated and integrated platform enables batch-supported compound synthesis based on a broad array of chemical transformations with testing in a variety of biochemical assay formats. A library turnaround time of between 24 and 36 h was achieved, and notably, each library synthesis produces sufficient amounts of compounds for further evaluation in secondary assays thereby contributing significantly to the shortening of medicinal chemistry discovery cycles.
Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity.A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.
A wide array of pharmaceutical research studies involve dispensing a variety of powders such as active ingredients, intermediates, catalysts, and formulation excipients. Automated powder dispensing platforms are increasingly relied upon to perform the mundane task of filling vials in multi-well plates for high-throughput experimentation workflows. A small group of pharmaceutical scientists collaborated to evaluate recent advances in commercially available automation platforms from two instrument manufacturers using previously reported objective and systematic testing protocols. This manuscript details the testing conditions used for the evaluation and the results obtained and assesses the impact that the powder characteristics had on the performance of the selected platforms through statistical analysis.
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