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Discovery of Novel Non-Statin-Based Cholesterol-Lowering Compound

The new compound exhibits a good safety profile and tolerability among individuals, providing an effective alternative for patients with statin intolerance.

Hyperlipidaemia, or a high level of lipids (fats) in the blood, is a major risk factor for atherosclerosis and coronary artery disease. Currently, lipid-lowering agents like statins are the main clinical treatment for hyperlipidaemia. While generally effective, the same cannot be said for about one-fifth of the patients with high levels of cholesterols or who have statin intolerance.

As the consumption of processed foods increases, as well as leading a sedentary lifestyle, cardio-metabolic diseases like hyperlipidaemias are also set to rise. Hence, developing non-statin-based cholesterol-lowering small compounds would be highly desirable.

In a study published in Cell Metabolism, a group of scientists from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences found a novel target for hyperlipidaemia and developed a novel lipid-lowering small compound DC371739, which exhibited a promising lipid-lowering effect in vitro and in vivo, as well as a good safety profile and tolerability in both healthy subjects and patients with hyperlipidaemia.

Their novel compound was derived from tetrahydroprotoberberines (THPBs) that were extracted from the Chinese herb Corydalis ambigua, which had previously demonstrated various biological activities. In previous works, they had made chemical modifications to THPBs and constructed a small compound library with different scaffolds. They then screened this library for hyperlipidaemic drug candidates and performed structure-activity relationship and drug-like property evaluation to identify their novel highly potent DC371739.

The team proved that the novel compound effectively reduced the total cholesterol and low-density lipoprotein (or “bad”) cholesterol in the serum of hyperlipidaemic hamsters and rhesus monkeys in a dose-dependent manner.

When compared to other lipid-lowering agents like berberine, DC371739 acts in a distinct manner. While oral administration of berberine can reduce serum total cholesterol and bad cholesterol in patients after three months of treatment, it requires a high oral dose, has poor bioavailability, and there is a potential for hERG potassium channel inhibitory activity. The team’s novel compound, on the other hand, displayed higher bioavailability than berberine and lower inhibition of hERG channel in vitro.

Furthermore, the team went on to combine the treatment of DC371739 with atorvastatin and found that the dual therapy promoted more lipid-lowering effects than either monotherapy, thus providing a potential therapeutic strategy for patients with atorvastatin intolerance. [APBN]

Source: Wang et al. (2022). Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial.Cell Metabolism,34(5), 667-680.