Automated iterative Csp3-C bond formation.

Fully automated synthetic chemistry would substantially change the field by providing broad on-demand access to small molecules. However, the reactions that can be run autonomously are still limited. Automating the stereospecific assembly of Csp3-C bonds would expand access to many important types of functional organic molecules1. Previously, methyliminodiacetic acid (MIDA) boronates were used to orchestrate the formation of Csp2-Csp2 bonds and were effective building blocks for automating the synthesis of many small molecules2, but they are incompatible with stereospecific Csp3-Csp2 and Csp3-Csp3 bond-forming reactions3-10. Here we report that hyperconjugative and steric tuning provide a new class of tetramethyl N-methyliminodiacetic acid (TIDA) boronates that are stable to these conditions. Charge density analysis11-13 revealed that redistribution of electron density increases covalency of the N-B bond and thereby attenuates its hydrolysis. Complementary steric shielding of carbonyl π-faces decreases reactivity towards nucleophilic reagents. The unique features of the iminodiacetic acid cage2, which are essential for generalized automated synthesis, are retained by TIDA boronates. This enabled Csp3 boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific Csp3-Csp2 and Csp3-Csp3 bond formation. These findings will enable increasingly complex Csp3-rich small molecules to be accessed via automated assembly.

Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis.

This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted.

An infrastructure for high-throughput microscopy: instrumentation, informatics, and integration.

High-throughput, image-based cell assays are rapidly emerging as valuable tools for the pharmaceutical industry and academic laboratories for use in both drug discovery and basic cell biology research. Access to commercially available assay reagents and automated microscope systems has made it relatively straightforward for a laboratory to begin running assays and collecting image-based cell assay data, but doing so on a large scale can be more challenging. Challenges include process bottlenecks with sample preparation, image acquisition, and data analysis as well as day-to-day assay consistency, managing unprecedented quantities of image data, and fully extracting useful information from the primary assay data. This chapter considers many of the decisions needed to build a robust infrastructure that addresses these challenges. Infrastructure components described include integrated laboratory automation systems for sample preparation and imaging, as well as an informatics infrastructure for multilevel image and data analysis. Throughout the chapter we describe a variety of strategies that emphasize building processes that are scaleable, highly efficient, and rigorously quality controlled.