👤 Muneto Mogi

Schematic presentation of possible mechanisms of hypertensive dementia, including amyloid beta metabolism (A), NVU dysfunction (B), vulnerability of the hippocampus (C), and activation of RAS (D), and possible new therapeutic approaches for discovering antihypertensive drugs with anti-dementia actions (E). See text for details. Aβ, amyloid β; APP, amyloid β precursor protein; BACE1, β-site amyloid precursor protein cleaving enzyme 1; BBB, blood-brain barrier; CBF, cerebral blood flow; eNOS, endothelial nitric oxide synthase; FDA, Food and Drug Administration; IL, interleukin; NOX, NADPH oxidase; NVU, neurovascular unit; RAS, renin-angiotensin system; ROS, reactive oxygen species. Show less

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. Show less