AI Article Synopsis
- - The research focuses on creating 2-phenylbenzoxazoles that inhibit cholesteryl ester transfer protein (CETP), aiming to reduce binding to hERG, which is often a safety concern for drug candidates.
- - Substituting the piperidine group with a cyclohexyl group decreased hERG binding but negatively impacted the effectiveness of the compounds in living organisms.
- - A new strategy using an oxazolidinone instead of piperidine showed promise, leading to compounds 7e and 7f that increased HDL cholesterol levels in transgenic mice while minimizing hERG risks.
Article 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.
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| http://dx.doi.org/10.1016/j.bmcl.2011.02.049 | DOI Listing |
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