The therapeutic potential of CETP inhibitors: a patent review

ABSTRACT

Introduction: Epidemiological studies have identified that high levels of low-density lipoprotein-cholesterol (LDL-C) and low levels of high-density lipoprotein-cholesterol (HDL-C) are two independent causes of cardiovascular disease (CVD). Statins, niacin and fibrate are used for the treatment of CVD. However, some defects are shown in the treatment process. Thus, there is a demand for better treatment strategies that confer preferable efficacy with fewer side effects. Cholesteryl ester transfer protein (CETP) promotes the movement of CEs from HDL to LDL and VLDL in exchange for triglycerides (TGs).

Areas covered: In this review, we reviewed the development and therapeutic applications of CETP inhibitors. A comprehensive review of the patents and pharmaceutical applications between 2009 and 2017 has been highlighted.

Expert opinion: Recently, CETP inhibitors have attracted considerable interest in atherosclerosis-related disease. There are four drugs (torcetrapib, anacetrapib, evacetrapib and dalcetrapib) that have been clinically evaluated in phase III clinical trials and showed promising results in raising HDL-C levels, but there were suboptimal performances in reducing the risk of cardiovascular events with all the compounds. The correlation between plasma HDL-C levels and CVD incidence needs further verification. The timeline is still long for CETP inhibitors to emerge from the treatment of CVD.

KEYWORDS:

• Cholesteryl ester transfer protein
• cardiovascular disease
• anacetrapib
• reverse cholesterol transport

Article highlights

• Cholesteryl ester transfer protein (CETP), a vital enzyme of reverse cholesterol transport, plays a role in regulating plasma lipids.

• Drug design strategies for developing CETP inhibitors have been considered an effective strategy to prevent dyslipidemia and cardiovascular disease.

• A comprehensive review of the patents and pharmaceutical applications on CETP inhibitors between 2009 and 2017 has been highlighted.

• CETP inhibitors are usually characterized by high lipophilicity and large molecular weights, which may cause drug accumulation in adipose tissue and a reduction in drugability. However, inhibitors with moderate lipophilicity and proper molecular weights are beneficial to avoid off-target effects and adverse effects.

• Four inhibitors did not appear to reduce cardiovascular risk in phase III clinical trials, though all of them apparently raised HDL-C levels. Cholesterol efflux capacity and non-HDL-C levels should be taken into account when predicting CVD risk.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

National Natural Science Foundation of China [grant number 81373324].