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Small Manufacturing Systems to Produce Research Grade Pharmaceutical Intermediates


(Fast-Track and Direct to Phase 2 proposals will not be accepted. Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning.) Number of anticipated awards: 2 to 3 Budget (total costs, per award): Phase I: $325,000 for 9 months; Phase II: $2,000,000 for 2 years It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary; Preclinical drug development is a time and cost-intensive process that involves synthesizing analogs as part of a medicinal chemistry drug discovery campaign. Typically, chemists in small and mid-sized laboratories are tasked with preparing multiple targets at the same time, relying on cumbersome batch synthesis methods in order to find key intermediates that can rapidly undergo the final transformations prior to biological testing. To reduce the steps to obtain the intermediate that will support structure-activity relationship (SAR) studies by medicinal chemists, the key pharmacophore or key structural component must be known where one can perform strategic chemical modification. The translational burden required in the process of synthesizing iterative rounds of analogs for biological screening activities can be alleviated by keeping to a minimum, the amount of work involved in tuning the synthesis of each new target. Often this can be achieved by identifying the shortest synthetic route, requiring the least number of isolation methods, while maintaining desired purity and yields for lead compounds. The key to accelerating molecules into the clinic is the ability to use automation to make the lead compound, and the early involvement of process chemists with medicinal chemists to identify the correct late-stage intermediate to produce the final drug target. Major advancements in the area of computer-aided drug discovery/design methods have proven to play a critical role in the development of therapeutically important small molecules in recent decades. Critical finished products such as pharmaceutical drugs rely on intermediate materials utilized to produce the bulk drug substance. Often vulnerable to supply chain disruptions, the availability of these important intermediates as starting materials, dictate production capabilities of critical pharmaceutical drug products in both local and national scenes, which in turn directly impact healthcare outcomes. This initiative seeks proposals from the small business community to support the development of compact tools and devices capable of manufacturing key chemical intermediates at the benchtop, for just-in-time delivery of such materials in quantities that optimally Page 76 impact the throughput of research operations. Using new or existing chemistries, in tandem with innovative solutions through engineering approaches, the purpose of this device is to speed up the preclinical drug development stage, by providing on-demand access to key intermediates that can be rapidly diversified to analogs or used to scale-up material for animal studies. Robust laboratory instruments that are amenable to automation and real-time data acquisition/monitoring will assist medicinal chemists in synthesizing critical intermediates. Like the development of peptide synthesizers in the mid-80’s, the paradigm shift envisioned in this project is an innovative platform capable of supporting a broad range of chemical transformations as opposed to a single transformation type (e.g. peptide synthesis), in a reliable manner suitable to automation. We seek to leverage trends in automation in synthetic chemistry to shift the way that common intermediates in medicinal chemistry are currently acquired in the laboratory. The innovative platform must incorporate creative solutions to address current limitations in reagent delivery systems, reagent formulations, and data interpretation through a versatile, reconfigurable system that utilizes step changes in the workflow based on the type of chemistries involved. This project also supports innovation for the acceleration of molecules into the drug development pipeline using these newly developed tools, in lieu of traditional synthetic chemistry efforts. This may potentially have implications in domestic supply chain availability of pharmaceutical intermediates, especially for those that are largely produced overseas. By shortening the design-synthesize-test cycle in drug discovery, this project aims to increase access to preclinical candidates and allow for more rapid exploration of chemical space surrounding a disease target.
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