Inhibition of acyl coenzyme A-cholesterol acyltransferase: a possible treatment of atherosclerosis?
Our full understanding of atherosclerosis and our ability to prevent its sequellae are incomplete. As a result, further investigation of novel antiatherosclerotic mechanisms and agents continues. Acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibition has been evaluated as a potential mechanism by which the current treatment arsenal may be expanded. ACAT is present in a variety of tissues and is responsible for catalyzing the conversion of free cholesterol to the more readily stored cholesteryl esters. Impressive lipid effects demonstrated in animals have not generally been demonstrated in human clinical trials. Partial ACAT inhibition with specific agents has resulted in lesion regression and decreased progression, whereas complete ACAT inhibition via genetic alterations has led to an exacerbation of cholesterol deposition in tissues in animal models. No ACAT inhibitor has yet been fully evaluated in human clinical trials for its impact on atherosclerotic disease progression. Several hurdles, such as sample size requirements needed to detect effect over background therapy and lack of sensitive surrogate efficacy markers, have served as a deterrent to the development of this class of investigational drug. However, with recent technologic advancements, more sensitive methods of measuring disease progression may be available. Human clinical trials are currently underway, with several agents reported in Phase II clinical trials. Within the next few years, results from these trials may determine whether or not ACAT inhibitors will be added to the list of treatment options for the prevention of atherosclerotic disease progression.
Heinonen
Therese M
TM
Pfizer Global Research, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. therese.heinonen@pfizer.com
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D002785:Sterol O-Acyltransferase