Avasimibe was a pharmaceutical compound once investigated for its potential in cardiovascular health. Researchers explored its potential to address certain aspects of cardiovascular health. Emerging from early 1990s drug design, it aimed to create new treatments for lipid-related conditions. Its journey through scientific study highlights the complex process of drug development.
Understanding Avasimibe
Avasimibe served as a drug candidate designed to influence the body’s lipid pathways. It belongs to a class of compounds known as acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors. This investigational compound was specifically developed to modulate how cholesterol is handled within cells.
The primary intention behind avasimibe’s design was to act as a lipid-lowering agent. Scientists aimed to create an orally available and water-soluble ACAT inhibitor, addressing limitations of earlier, more lipophilic compounds. It resulted from rational drug design, seeking to develop agents that could intervene in cholesterol metabolism.
The Mechanism of ACAT Inhibition
The enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) plays a direct role in the body’s cholesterol metabolism, cholesterol esterification. This process involves converting free cholesterol into cholesterol esters, stored within cells in lipid droplets. ACAT exists in two main forms, ACAT1 and ACAT2, both contributing to this cellular cholesterol management. Avasimibe was engineered to specifically block the activity of these ACAT enzymes.
By inhibiting ACAT, avasimibe was intended to reduce the formation and storage of cholesterol esters inside various cell types. This mechanism was hypothesized to modify intracellular cholesterol levels, potentially preventing the excessive accumulation of cholesterol. In laboratory studies involving human macrophages, avasimibe was observed to decrease the formation of foam cells by both enhancing cholesterol efflux and reducing the uptake of modified low-density lipoprotein (LDL). The compound also showed an ability to reduce the secretion of apolipoprotein B (apo B) and apo B-containing lipoproteins from the liver.
Avasimibe’s Target Condition
Avasimibe was primarily developed to address atherosclerosis, a chronic condition affecting the arteries. Atherosclerosis occurs when plaque, a fatty substance composed largely of cholesterol, builds up on the inner walls of arteries. This buildup can narrow the arteries, restricting blood flow and potentially leading to serious cardiovascular events such as heart attacks and strokes.
The connection between ACAT inhibition and atherosclerosis centered on reducing cholesterol accumulation within arterial walls. By inhibiting cholesterol esterification, avasimibe was hypothesized to limit the amount of cholesterol stored in cells that contribute to plaque formation. This action aimed to reduce the lipid burden in the arteries, slowing or preventing atherosclerotic lesion progression. Preclinical studies in animal models, such as ApoE3-Leiden mice, showed that avasimibe could reduce atherosclerosis by significantly lowering lesion areas, sometimes by as much as 92%, suggesting a direct anti-atherosclerotic activity.
Development and Research Findings
Avasimibe’s development involved several stages of clinical trials after its initial description in 1996. Phase I trials began in 1997 for hyperlipidemia and later for atherosclerosis. These early studies progressed to Phase II trials in 1998, and by 2001, avasimibe entered Phase III clinical development.
Despite promising preclinical data and initial safety observations in human studies, the clinical development of avasimibe was discontinued in October 2003. A pivotal study indicated that avasimibe did not favorably alter coronary atherosclerosis, as assessed by intravascular ultrasound (IVUS), and unexpectedly led to a mild increase in LDL cholesterol levels. Additionally, the compound showed a high potential for interactions with other medications, acting as an indirect inducer of certain cytochrome P450 enzymes and an inhibitor of others, which presented safety concerns. These findings collectively led to the decision to halt its progression to market.