Despite recent advances in the field of C­(sp2)–C­(sp3) cross-couplings and the accompanying increase in publications, it can be hard to determine which method is appropriate for a given reaction when using the highly functionalized intermediates prevalent in medicinal chemistry. Thus a study was done comparing the ability of seven methods to directly install a diverse set of alkyl groups on “drug-like” aryl structures via parallel library synthesis. Each method showed substrates that it excelled at coupling compared with the other methods. When analyzing the reactions run across all of the methods, a reaction success rate of 50% was achieved. Whereas this is promising, there are still gaps in the scope of direct C­(sp2)–C­(sp3) coupling methods, like tertiary group installation. The results reported herein should be used to inform future syntheses, assess reaction scope, and encourage medicinal chemists to expand their synthetic toolbox.

The field of flow chemistry has garnered considerable attention over the past 2 decades. This Perspective highlights many recent advances in the field of flow chemistry and discusses applications to the pharmaceutical industry, from discovery to manufacturing. From a synthetic perspective, a number of new enabling technologies are providing more rationale to run reactions in flow over batch techniques. Additionally, highly automated flow synthesis platforms have been developed with broad applicability across the pharmaceutical industry, ranging from advancing medicinal chemistry programs to self-optimizing synthetic routes. A combination of simplified and automated systems is discussed, demonstrating how flow chemistry solutions can be tailored to fit the specific needs of a project.

Noncompressible torso hemorrhage is a leading cause of mortality in civilian and battlefield trauma. We sought to develop an i.v.-injectable, tissue factor (TF)-targeted nanotherapy to stop hemorrhage. Tissue factor was chosen as a target because it is only exposed to the intravascular space upon vessel disruption. Peptide amphiphile (PA) monomers that self-assemble into nanofibers were chosen as the delivery vehicle. Three TF-binding sequences were identified (EGR, RLM, and RTL), covalently incorporated into the PA backbone, and shown to self-assemble into nanofibers by cryo-transmission electron microscopy. Both the RLM and RTL peptides bound recombinant TF in vitro. All three TF-targeted nanofibers bound to the site of punch biopsy-induced liver hemorrhage in vivo, but only RTL nanofibers reduced blood loss versus sham (53% reduction, p < 0.05). Increasing the targeting ligand density of RTL nanofibers yielded qualitatively better binding to the site of injury and greater reductions in blood loss in vivo (p < 0.05). In fact, 100% RTL nanofiber reduced overall blood loss by 60% versus sham (p < 0.05). Evaluation of the biocompatibility of the RTL nanofiber revealed that it did not induce RBC hemolysis, did not induce neutrophil or macrophage inflammation at the site of liver injury, and 70% remained intact in plasma after 30 min. In summary, these studies demonstrate successful binding of peptides to TF in vitro and successful homing of a TF-targeted PA nanofiber to the site of hemorrhage with an associated decrease in blood loss in vivo. Thus, this therapeutic may potentially treat noncompressible hemorrhage.

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...

Parallel library synthesis is an important tool for drug discovery because it enables the synthesis of closely related analogues in parallel via robust and general synthetic transformations. In this perspective, we analyzed the synthetic methodologies used in >5000 parallel libraries representing 15 prevalent synthetic transformations. The library data set contains complex substrates and diverse arrays of building blocks used over the last 14 years at AbbVie. The library synthetic methodologies that have demonstrated robustness and generality with proven success are described along with their substrate scopes. The evolution of the synthetic methodologies for library synthesis over the past decade is discussed. We also highlight that the combination of parallel library synthesis with high-throughput experimentation will continue to facilitate the discovery of library-amenable synthetic methodologies in drug discovery.

A simplified Boc deprotection using a high-temperature flow reactor is described. The system afforded the qualitative yield of a wide variety of deprotected substrates within minutes using acetonitrile as the solvent and without the use of acidic conditions or additional workups. Highly efficient, multistep reaction sequences in flow are also demonstrated wherein no extraction or isolation was required between steps.

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand–receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.

A photo-flow Norrish-Yang cyclisation has been devised that delivers 3-hydroxyazetidines in good yields. The high reproducibility and short residence times of the flow process enables easy scaling of the transformation allowing access to these valuable chemical entities at synthetically useful multi-gram scales. A systematic exploration of the constituent structural components was undertaken allowing an understanding of the reactivity and functional group tolerance of the transformation.