Process Development of a Potent Glucosylceramide Synthase Inhibitor

An economic, scalable process for the production of glucosylceramide synthase (GCS) inhibitor <b>7</b> has been developed. Herein we report a three-step synthesis to aldehyde <b>4</b> with high yield and purity that employs the selective cleavage of an endocyclic C–O bond of a THP ether using borane/THF as the key step. This particular methodology has not been used previously from a development standpoint and offers an attractive way towards introducing pentanol side chains. Aldehyde <b>4</b> is then coupled with deoxynojirimycin <i>via</i> flow hydrogenation using an H-Cube to safely produce the free base of <b>7</b>, which is isolated as an MSA salt in 50% overall yield. Herein we discuss the evolution of this process from its original form and the thermodynamics of its associated chemistry

Inter-rater agreement and reliability of the assessment of lithium response in the two-stage case-vignette rating procedure: kappa and intra-class correlation analysis.

<p>TS: total score.</p><p>ICC: intra-class correlation.</p><p>CI: confidence interval.</p>*<p>Mixed and random effects models.</p>§<p>70 raters.</p>¶<p>48 raters.</p

Empirical and theoretical distributions of the total score in the Consortium on Lithium Genetics sample.

<p>Frequentist, <b>A</b>, and Bayesian minimum message length, <b>B</b>, mixture modeling identify three subpopulations of non responders (grey), partial responders (red), and full responders (blue) in total scores of 1,308 bipolar disorder patients characterized for response to lithium maintenance treatment.</p

Number of raters from the Consortium on Lithium Genetics (ConLiGen) centres participating in the two-stage case-vignette rating procedure for inter-rater reliability and agreement.

<p>ConLiGen: Consortium on Lithium Genetics.</p>*<p>Hokkaido, Osaka, Tokio, Riken Brain Science Institute.</p

Distribution of total and A scores in the Consortium on Lithium Genetics sample.

<p>Histogram plot of the scale scores in 1,308 bipolar disorder patients characterized for response to lithium maintenance treatment.</p