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2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy
- Source :
- Bioorganicmedicinal chemistry letters. 21(9)
- Publication Year :
- 2010
-
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.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
Stereochemistry
medicine.drug_class
Clinical Biochemistry
hERG
Pharmaceutical Science
Carboxamide
Mice, Transgenic
Biochemistry
Chemical synthesis
chemistry.chemical_compound
Inhibitory Concentration 50
Mice
Structure-Activity Relationship
Transcriptional Regulator ERG
Drug Discovery
Cholesterylester transfer protein
medicine
Structure–activity relationship
Moiety
Animals
cardiovascular diseases
Molecular Biology
Benzoxazoles
biology
Molecular Structure
Organic Chemistry
Cholesterol, HDL
Benzoxazole
Cholesterol Ester Transfer Proteins
chemistry
biology.protein
Trans-Activators
Molecular Medicine
Piperidine
Protein Binding
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 21
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....834dd9cec4ea3b0388f8639d3c2277b5