title: Discovery of benzothiazole derivatives as efficacious and enterocyte-specific MTP inhibitors.
abstract: A series of triamide derivatives bearing a benzothiazole core is shown to be potent microsomal triglyceride transfer protein (MTP) inhibitors. In order to minimize liver toxicity, these compounds have been optimized to have activity only in the enterocytes and have limited systemic bioavailability. Upon oral administration, selected analogs within this series have been further demonstrated to reduce food intake along with body weight and thereby improve glucose homeostasis and insulin sensitivity in a 28-day mice diet-induced obesity (DIO) model.
authors.affiliation: Sirtris Pharmaceuticals, Departments of Medicinal Chemistry, Lead Discovery and Pharmacology, 200 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Chi B
authors.initials: CB
authors.lastname: Vu
authors.forename: Jill C
authors.initials: JC
authors.lastname: Milne
authors.forename: David P
authors.initials: DP
authors.lastname: Carney
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Song
authors.forename: Wendy
authors.initials: W
authors.lastname: Choy
authors.forename: Philip D
authors.initials: PD
authors.lastname: Lambert
authors.forename: David J
authors.initials: DJ
authors.lastname: Gagne
authors.forename: Michael
authors.initials: M
authors.lastname: Hirsch
authors.forename: Angela
authors.initials: A
authors.lastname: Cote
authors.forename: Meghan
authors.initials: M
authors.lastname: Davis
authors.forename: Elden
authors.initials: E
authors.lastname: Lainez
authors.forename: Nekeya
authors.initials: N
authors.lastname: Meade
authors.forename: Karl
authors.initials: K
authors.lastname: Normington
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jirousek
authors.forename: Robert B
authors.initials: RB
authors.lastname: Perni
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D055808:Drug Discovery; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D052160:Benzothiazoles; D002352:Carrier Proteins; C106092:microsomal triglyceride transfer protein