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2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy |
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| Authors: | Sweis Ramzi F Hunt Julianne A Sinclair Peter J Chen Ying Eveland Suzanne S Guo Qiu Hyland Sheryl A Milot Denise P Cumiskey Anne-Marie Latham Melanie Rosa Raymond Peterson Larry Sparrow Carl P Anderson Matt S |
| Affiliation: | a Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA b Department of Cardiovascular Diseases, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA c Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA |
| 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 27 mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series. |
| Keywords: | Cholesteryl ester transfer protein Cholesterol hERG HDLc LDLc Atherosclerosis |
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