Inhibitors of diacylglycerol acyltransferase: a review of 2008 patents.
BACKGROUND
Postprandial hypertriglyceridemia has been identified as a major independent risk factor for future cardiovascular events. Therefore, inhibition of triglyceride synthesis has enormous therapeutic potential in the treatment of metabolic disorders. Diacylglycerol acyltransferase (DGAT) enzymes catalyze the final and only committed step in triglyceride biosynthesis and have thus been identified as potential therapeutic targets to combat human cardio-metabolic diseases.


OBJECTIVE
Significant interest in DGAT-1 inhibitors has emerged in the last several years. To provide a perspective on the exciting features of this enzyme for targeting metabolic diseases, a summary of the biology and pharmacology surrounding the DGAT enzymes is presented. Following this is a discussion of the various chemotypes that have been disclosed within relevant patent applications published in 2008. Specifically, the similarities and differences of the chemical structures and the biological data that are provided to support the corresponding claims are presented.


CONCLUSIONS
Small molecule and biologic-based DGAT inhibitors have been successfully used for the preclinical validation of DGAT enzymes as targets for the treatment of metabolic diseases. Given the advanced stage in which some of the chemical matter resides, it is expected that DGAT inhibitors will enter the clinic in the coming years.
King
Andrew J
AJ
Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
Judd
Andrew S
AS
Souers
Andrew J
AJ
D000818:Animals; D001688:Biological Products / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000503:physiopathology / Q000517:prevention & control; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D016503:Drug Delivery Systems; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015228:Hypertriglyceridemia / Q000150:complications / Q000188:drug therapy; D008659:Metabolic Diseases / Q000503:physiopathology / Q000517:prevention & control; D010330:Patents as Topic; D012307:Risk Factors
D001688:Biological Products; D004791:Enzyme Inhibitors; D051048:Diacylglycerol O-Acyltransferase