Abstract
Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC50 = 0.79 ± 0.02 μM) in vitro and showed an acceptable metabolic stability.
Highlights
Robust evidence suggests that a high level of low-density lipoprotein cholesterol (LDL-C) and a low level of high-density lipoprotein cholesterol (HDL-C) are closely associated with cardiovascular disease (CVD) [1,2,3,4]
Despite the successful utilization of statins in clinical treatment for reducing LDL-C levels, the residual risk of CVD events remains at high levels [7,8,9,10]
Plasma cholesteryl ester transfer protein (CETP), secreted mainly from the liver, plays a coordinating part in reverse cholesteryl transfer (RCT) that facilitates the transfer of triglyceride and cholesteryl ester (CE) between lipoproteins
Summary
Robust evidence suggests that a high level of low-density lipoprotein cholesterol (LDL-C) and a low level of high-density lipoprotein cholesterol (HDL-C) are closely associated with cardiovascular disease (CVD) [1,2,3,4]. In contrast to LDL-C, the risk of cardiovascular events will be reduced 2% to 3% for each 0.1 mg/dL increase in HDL-C [6]. The elevation of HDL-C via inhibiting CETP is an effective strategy for reducing the risk of cardiovascular events. The phase clinical trial was terminated due the fact that dalcetrapib did not significantly decrease the risk of cardiovascular events [15,16]. Torcetrapib, effectively reduced LDL-C levels by 45.3%, and increased HDL-C levels by 179.1% [18]. Found that compound exhibited weak inhibition activity. 17d with with aa fragments seven fragments revealed a slight increase in activity, and the replacement of compound 17d with a.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
