Structural optimization of cholesteryl ester transfer protein inhibitors: From early scaffolds to advanced clinical...

Cholesteryl ester transfer protein has been a long-sought target for the treatment of dyslipidemia because of its prime function in the remolding of lipoprotein particles and the reverse transport of cholesterol. During the past couple of decades, a huge variety of CETP inhibitors has been generated from intensive biomedical research, taking on diverse primary scaffolds from discovery to late-stage development. Despite their promising beginnings, the first-generation CETP inhibitors have been realized to possess a couple of obvious flaws, such as the existence of off-target toxicities, high lipophilicity, sub-optimized pharmacokinetic properties, and inconsistent results in the outcomes of clinical studies, leading to the termination of a couple of candidates in late-stage development. Therefore, the need for the next-generation approach that considered optimizations in the pharmacokinetics and physiological-chemical properties and the reduction of ligand efficiency and primary scaffolds allowed for the development of pharmacokinetic and late-stage CETP inhibitors with enhanced properties. Here, a thorough discussion to analyze the leveraging of biomedical principles to further develop late-generation CETP inhibitors with major improvements from the pharmacokinetics and results of the primary clinical studies characterizing a huge variety of the first-generation CETP inhibitors with diverse primary bioactive scaffolds will be undertaken.