Discovery of a Novel Piperidine-Based Inhibitor of Cholesteryl Ester Transfer Protein (CETP) That Retains Activity in Hypertriglyceridemic Plasma

Abstract

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.

High-Density Lipoprotein Subfractions Remodeling: A Critical Process for the Treatment of Atherosclerotic Cardiovascular Diseases

“…It may also be that anacetrapib reduces plasma levels of the proprotein convertase subtilisin kexin type 9 (PCSK9), which is one of the major regulators of LDLR. 97 Although the REVEAL trial has shown that anacetrapib could reduce the risk of major coronary events, as it is highly lipophilic and accumulated in adipose tissue during continued dosing 98 ; further regulatory approval is not be sought. Despite the development of effective HDL-raising drugs, large-scale clinical trials showed disappointing results with no significant reduction of clinical CV events.…”

Pd-Catalyzed Cross-Couplings: On the Importance of the Catalyst Quantity Descriptors, mol % and ppm

“…As a comparison to the previous data set, ca. 15 additional papers were surveyed from the Journal of Medicinal Chemistry ( JMC ) for both SMCC reactions ,,− and Buchwald–Hartwig amination reactions. − ,− As the previous data were found from a variety of journals, although largely catalysis specific, we were interested to see how different these would be compared to papers only reported in JMC and if there was a difference in mol % and ppm catalyst levels. Finding more papers with a greater focus on catalyst usage, rather than catalyst optimization, reveals a different angle to this study.…”

Development of new oil/water partitioning tracers for the determination of residual oil saturation in the inter-well region of water-flooded reservoirs

“…Pyridine is frequently used in the chemical industry, primarily in the production of pesticides, as solvent, in the production of dyes, explosives, pharmaceuticals, and as ligand in specialty coordination chemistry synthesis (Ahsan et al, 2018;Liu et al, 1998;Shen et al, 2015). 4METPYR has been reported as ligand in coordination chemistry (Mautner et al, 2018) and as precursor for the synthesis of active principles by the pharmaceutical industry (Yamada et al, 2017). 3HYPYR has been investigated as a monomer for production of polymers for CO2 capture (Gutiérrez et al, 2011), but its primary use is as precursor for pharmaceutical active principles (Kaviani and Izadyar, 2018).…”