Defining the key pharmacophore elements of PF-04620110: Discovery of a potent, orally-active, neutral DGAT-1 inhibitor

DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical tri...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-09, Vol.21 (17), p.5081-5097
Main Authors: Dow, Robert L., Andrews, Melissa P., Li, Jian-Cheng, Michael Gibbs, E., Guzman-Perez, Angel, LaPerle, Jennifer L., Li, Qifang, Mather, Dawn, Munchhof, Michael J., Niosi, Mark, Patel, Leena, Perreault, Christian, Tapley, Susan, Zavadoski, William J.
Format: Article
Language:English
Subjects:
Administration, Oral
animal models
Animals
Carboxylic acid bioisotere
chemistry
Clinical trials
DGAT-1
Diabetes
Diacylglycerol O-Acyltransferase - antagonists & inhibitors
Diacylglycerol O-Acyltransferase - metabolism
Drug Evaluation, Preclinical
enzyme inhibitors
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - therapeutic use
Half-Life
Humans
messenger RNA
Mice
Mice, Inbred C57BL
Mice, Obese
noninsulin-dependent diabetes mellitus
Obesity
Obesity - drug therapy
Oxadiazoles - chemistry
Oxazepines - chemistry
Oxazepines - pharmacokinetics
Oxazepines - therapeutic use
Passive permeability
permeability
pharmacology
Polar surface area
Protein Binding
Rats
Structure-Activity Relationship
triacylglycerols
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.06.045