The class
Oxazolidinone-substituted benzoxazole CETP inhibitors raise HDL cholesterol up to 33 mg/dl in mice while avoiding hERG channel binding (Bioorg Med Chem Lett 2011)
Original title: 2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy
In developing 2-phenylbenzoxazole inhibitors of cholesteryl ester transfer protein (CETP), efforts focused on replacing the central piperidine of the benchmark compound to reduce hERG channel binding, its main liability. Substituting piperidine with a cyclohexyl group attenuated hERG binding but reduced in vivo efficacy, while substituting an oxazolidinone also attenuated hERG binding. Further refinement of the oxazolidinone scaffold through structure-activity relationship studies at the pyridine terminus and methyl branching produced compounds 7e and 7f, which raised HDL cholesterol by 33 and 27 mg/dl, respectively, in a transgenic mouse pharmacodynamic model, without the hERG liability of previous compound series.
Original abstract
The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.