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.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Glucosyltransferases/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Animals , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Gangliosides/metabolism , Glucose Tolerance Test , Glucosyltransferases/metabolism , Humans , Liver/drug effects , Liver/enzymology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mice, Nude , Phenylalanine/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Zucker , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glucosyltransferases/antagonists & inhibitors , Glucosyltransferases/metabolism , Administration, Oral , Animals , Drug Discovery , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Humans , Mice , Mice, Inbred C57BL , Structure-Activity RelationshipABSTRACT
Fungal biotransformations of alpha-santonin (1) were conducted with Mucor plumbeus (ATCC 4740), Cunninghamella bainieri (ATCC 9244), Cunninghamella echinulata (ATCC 9245), Curvularia lunata (ATCC 12017) and Rhizopus stolonifer (ATCC 10404). Rhizopus stolonifer (ATCC 10404) metabolized compound 1 to afford 3,4-epoxy-alpha-santonin (2) and 4,5-dihydro-alpha-santonin (3) while Cunninghamella bainieri (ATCC 9244), Cunninghamella echinulata (ATCC 9245) and Mucor plumbeus (ATCC 4740) were capable of metabolizing compound 1 to give a reported metabolite, 1,2-dihydro-alpha-santonin (4). The structures of these transformed metabolites were established with the aid of extensive spectroscopic studies. These fungi regiospecifically reduced the carbon-carbon double bond in ring A of alpha-santonin.
