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Discovery of a Novel Piperidine-Based Inhibitor of Cholesteryl Ester Transfer Protein (CETP) That Retains Activity in Hypertriglyceridemic Plasma
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 <b>16</b> (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