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Cassidy, Shawn M.; Ramaswamy, Manisha; Kennedy, Allison L.; Strobel, Frank W.; Ng, Samson; Lee, Tak-Yee

doi:10.1023/a:1011951602894

Cited by 25 publications

(1 citation statement)

References 9 publications

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“…Lipoprotein fractions were isolated from serum by density gradient ultracentrifugation, according to Wasan et al, with minor modifications. NaBr (0.36 g/mL) was added to serum containing 500 ng/mL of CETP inhibitor.…”

Section: Methodsmentioning

confidence: 99%

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

Yamada

Brousseau²,

Honma

et al. 2017

J. Med. Chem.

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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.

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Section: Methodsmentioning

confidence: 99%