The class
A review traces how CETP-inhibitor design evolved from first-generation scaffolds plagued by off-target toxicity to optimized late-generation clinical candidates (Eur J Med Chem 2026)
Original title: Structural optimization of cholesteryl ester transfer protein inhibitors: From early scaffolds to advanced clinical candidates
This review examines the structural optimization of CETP inhibitors, a long-sought dyslipidemia target due to its central role in remodeling lipoprotein particles and reverse cholesterol transport. Over the past two decades, intensive research generated a wide variety of CETP inhibitors spanning diverse primary chemical scaffolds, from early discovery compounds to late-stage clinical candidates. Despite promising beginnings, first-generation CETP inhibitors were found to carry clear flaws, including off-target toxicities, high lipophilicity, suboptimal pharmacokinetic properties, and inconsistent clinical trial outcomes, leading to termination of several late-stage candidates. The review discusses how a next-generation medicinal chemistry approach, optimizing pharmacokinetic and physicochemical properties and refining ligand efficiency across primary scaffolds, enabled development of later-generation CETP inhibitors with substantially improved pharmacokinetic profiles, analyzing this evolution across the diverse bioactive scaffolds explored throughout the class's history.
Original abstract
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.
the classmechanismspharmacology
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.