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Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC(50) of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.

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To probe for free radical intermediates in the model methylmalonate to succinate rearrangements promoted by vitamin B12., a model series with a pentenyl side chain radical trap has been devised. The control free radical, generated by tri-n-butyltin hydride treatment of bromomethylpentenylmalonate thioester, undergoes rapid cyclization to the six-membered ring, and, as anticipated, no succinate rearrangement product is detected. By contrast when the bromide is treated with vitamin B12., little cyclized product is observed;

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