title: Discovery and characterization of an inhibitor of glucosylceramide synthase.
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.
authors.affiliation: Exelixis, Inc., 210 E. Grand Avenue, South San Francisco, California 94080, USA. sjr.researcher@gmail.com
authors.forename: Steven
authors.initials: S
authors.lastname: Richards
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Larson
authors.forename: Elena S
authors.initials: ES
authors.lastname: Koltun
authors.forename: Art
authors.initials: A
authors.lastname: Hanel
authors.forename: Vicky
authors.initials: V
authors.lastname: Chan
authors.forename: Jason
authors.initials: J
authors.lastname: Nachtigall
authors.forename: Amanda
authors.initials: A
authors.lastname: Harrison
authors.forename: Naing
authors.initials: N
authors.lastname: Aay
authors.forename: Hongwang
authors.initials: H
authors.lastname: Du
authors.forename: Arlyn
authors.initials: A
authors.lastname: Arcalas
authors.forename: Adam
authors.initials: A
authors.lastname: Galan
authors.forename: Jeff
authors.initials: J
authors.lastname: Zhang
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Kwang-Ai
authors.initials: KA
authors.lastname: Won
authors.forename: Danny
authors.initials: D
authors.lastname: Tam
authors.forename: Fawn
authors.initials: F
authors.lastname: Qian
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Patricia
authors.initials: P
authors.lastname: Finn
authors.forename: Kathy
authors.initials: K
authors.lastname: Ogilvie
authors.forename: Jon
authors.initials: J
authors.lastname: Rosen
authors.forename: Ron
authors.initials: R
authors.lastname: Aoyama
authors.forename: Artur
authors.initials: A
authors.lastname: Plonowski
authors.forename: Belinda
authors.initials: B
authors.lastname: Cancilla
authors.forename: Frauke
authors.initials: F
authors.lastname: Bentzien
authors.forename: Michael
authors.initials: M
authors.lastname: Yakes
authors.forename: Raju
authors.initials: R
authors.lastname: Mohan
authors.forename: Peter
authors.initials: P
authors.lastname: Lamb
authors.forename: John
authors.initials: J
authors.lastname: Nuss
authors.forename: Patrick
authors.initials: P
authors.lastname: Kearney
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D005951:Glucose Tolerance Test; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
chemical_list: D004791:Enzyme Inhibitors; D005732:Gangliosides; D014280:Triglycerides; D010649:Phenylalanine; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase