Discovery and characterization of an inhibitor of glucosylceramide synthase.

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Richards S, Larson CJ, Koltun ES, Hanel A, Chan V, Nachtigall J, Harrison A, Aay N, Du H, Arcalas A, Galan A, Zhang J, Zhang W, Won KA, Tam D, Qian F, Wang T, Finn P, Ogilvie K, Rosen J, Aoyama R, Plonowski A, Cancilla B, Bentzien F, Yakes M, Mohan R, Lamb P, Nuss J, Kearney P

Discovery and characterization of an inhibitor of glucosylceramide synthase.

J Med Chem. 2012 May 10;55(9):4322-35. doi: 10.1021/jm300122u. Epub 2012 Apr 19.

PubMed ID

22497444 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Miglustat	Ceramide glucosyltransferase	IC 50 (nM)	22000	N/A	N/A	Details