High-throughput (HT) techniques built upon laboratory automation technology and coupled to statistical experimental design and parallel experimentation have enabled the acceleration of chemical process development across multiple industries. HT technologies are often applied to interrogate wide, often multidimensional experimental spaces to inform the design and optimization of any number of unit operations that chemical engineers use in process development. In this review, we outline the evolution of HT technology and provide a comprehensive overview of how HT automation is used throughout different industries, with a particular focus on chemical and pharmaceutical process development. In addition, we highlight the common strategies of how HT automation is incorporated into routine development activities to maximize its impact in various academic and industrial settings.
BMS-911543 is a complex pyrrolopyridine investigated as a potential treatment for myeloproliferative disorders. The development of a short and efficient synthesis of this molecule is described. During the course of our studies, a Ni-mediated C-N bond formation was invented, which enabled the rapid construction of the highly substituted 2-aminopyridine core. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only eight steps starting from readily available materials.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) in which neuropathic pain is now recognized as a major symptom. To date, few studies have examined the underlying mechanisms of neuropathic pain in MS. Recently we showed that in a chronic-relapsing animal model of MS, experimental autoimmune encephalomyelitis (EAE), characteristic neuropathic behaviours develop. However, responses to persistent noxious stimuli in EAE remain unexplored. We, therefore set out to characterize the changes in pain sensitivity in our EAE model to subcutaneous injection of formalin. We show here that female C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG(35-55)) display a significant decrease in elicited pain behaviours in response to formalin injection. These effects were found to involve dysregulation of the glutamatergic system in EAE. We show here that these effects are mediated by decreased glutamate transporter expression associated with EAE. Our findings demonstrate that dysregulation of glutamate transporter function in EAE mice is an important mechanism underlying the abnormal pain sensitivity in response to persistent noxious stimulation of mice with EAE and also sheds light on a potential mechanism underlying neuropathic pain behaviours in this model.
A catalytic, enantioselective γ -alkylation of α,β-unsaturated malonates and ketoesters is reported. This strategy entails a highly regio- and enantioselective iridium-catalyzed α-alkylation of an extended enolate, and a subsequent translocation of chirality to the γ-position via a Cope rearrangement.
The
development of an improved short and efficient commercial synthesis
of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described.
During the discovery and development of this synthesis, a Pd-catalyzed
C–H functionalization was invented which enabled the rapid
union of the key pyrrole and imidazole fragments. The synthesis of
this complex, nitrogen-rich heterocycle was accomplished in only six
steps (longest linear sequence) from readily available materials.
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