Discovery of benzothiazole derivatives as efficacious and enterocyte-specific MTP inhibitors.
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.
Vu
Chi B
CB
Sirtris Pharmaceuticals, Departments of Medicinal Chemistry, Lead Discovery and Pharmacology, 200 Technology Square, Cambridge, MA 02139, USA.
Milne
Jill C
JC
Carney
David P
DP
Song
Jeffrey
J
Choy
Wendy
W
Lambert
Philip D
PD
Gagne
David J
DJ
Hirsch
Michael
M
Cote
Angela
A
Davis
Meghan
M
Lainez
Elden
E
Meade
Nekeya
N
Normington
Karl
K
Jirousek
Michael R
MR
Perni
Robert B
RB
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
D052160:Benzothiazoles; D002352:Carrier Proteins; C106092:microsomal triglyceride transfer protein