Development of HMG-CoA Reductase Inhibitors for Cardiovascular Diseases

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are widely used clinically to lower cholesterol levels and prevent cardiovascular disease. Ace Therapeutics has long focused on cardiovascular drug discovery and development, and is committed to providing development and research services of HMG-CoA reductase inhibitors.

The Role of HMG-CoA Reductase in Cardiovascular Diseases

HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis, catalyzing the conversion of HMG-CoA to mevalonate, which is a critical step in cholesterol production. As a key target for lipid-modulating drugs, HMG-CoA reductase inhibitors competitively block this conversion, reducing mevalonate synthesis and subsequently lowering cholesterol levels in the body. This mechanism significantly decreases the risk of cardiovascular diseases, making HMG-CoA reductase a vital therapeutic target.

Fig. 1 Proposed molecular mechanisms involved in hypocholesterolemic effects of Mikania micrantha stem extract (EAMMS) via inhibition of hepatic lipid accumulation, lipid peroxidation, HMG-CoA reductase (HMGCR) and ACAT2; leading to a decrease of cholesterol concentration. (Ibrahim A, et al., 2020)

Current Status of HMG-CoA Reductase Inhibitor Development

HMG-CoA reductase inhibitors are widely used to manage a range of conditions, including dyslipidemia, hypertension, hypercholesterolemia, hyperlipoproteinemia, and chronic heart failure. Below, we highlight some of the most promising HMG-CoA reductase inhibitors currently in development.

HMG-CoA Reductase Inhibitors in Development or Approved for the Treatment of Cardiovascular Diseases

Discovery of HMG-CoA Reductase Inhibitors

Based on our professional technology platform, we can support our clients develop various types of HMG-CoA reductase inhibitors.

• Small Molecule Drug
  Small molecule drugs represent a major class of HMG-CoA reductase inhibitors. By targeting HMG-CoA reductase with precision, we help our clients develop small molecule inhibitors with enhanced drug selectivity, minimizing off-target effects and maximizing therapeutic efficacy.
• Gene Silencing Therapy
  In addition to small molecule approaches, we offer tailored drug discovery services using siRNA and ASO technologies. These gene silencing strategies provide a promising avenue for inhibiting HMG-CoA reductase expression, opening new possibilities for innovative and effective therapies.

In Vitro Pharmacodynamic Studies

• Enzyme Inhibition Assay
  Under controlled in vitro conditions, we can evaluate the inhibitory effect of drug candidates on HMG-CoA reductase activity. This allows us to determine the IC₅₀ value, a critical measure of the compound's potency and efficacy in blocking cholesterol biosynthesis.
• Effect on Cholesterol Synthesis
  Using liver cell lines such as HepG2, we can investigate the impact of drug candidates on genes involved in cholesterol metabolism. This approach enables us to detect their ability to inhibit cholesterol synthesis, providing valuable insights into their therapeutic potential.

In Vivo Pharmacodynamic Studies

• Effect on Hypercholesterolemia
  To assess the cholesterol-lowering effects of HMG-CoA reductase inhibitors, we can construct high-fat diet-induced hypercholesterolemia models. These models closely mimic human metabolic conditions, allowing us to evaluate the efficacy of drug candidates in reducing cholesterol levels.
• Effect on Atherosclerosis
  Using genetically modified animal models, such as LDL-R knockout mice and ApoE knockout mice, we can evaluate the interventional effects of test drugs, providing critical data on their ability to modulate disease progression of atherosclerosis.
• Effect on Hypertension
  We utilize SPF class spontaneously hypertensive rats (SHR) to construct robust models of hypertension. Through comprehensive assessments including blood pressure monitoring, echocardiographic measurements, lipid profile evaluation, and inflammatory factor analysis, we can evaluate the modulatory effects of HMG-CoA reductase inhibitors on hypertension and associated cardiovascular risks.

Ace Therapeutics is dedicated to providing HMG-CoA reductase inhibitor development researchers with professional preclinical research services, including in vitro assays and animal studies. If you are interested in our services, please do not hesitate to contact us.

1. Ibrahim, A.; et al. Mikania micrantha Extract Inhibits HMG-CoA Reductase and ACAT2 and Ameliorates Hypercholesterolemia and Lipid Peroxidation in High Cholesterol-Fed Rats. Nutrients. 2020, 12(10):3077.