Bioorganic & medicinal chemistry letters, 2013-08, Vol.23 (16), p.4627-4632
2013
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Details
- Autor(en) / Beteiligte
- Titel
- Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists
- Ist Teil von
- Bioorganic & medicinal chemistry letters, 2013-08, Vol.23 (16), p.4627-4632
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2013
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- A series of non-steroidal GPBAR1 (TGR5) agonists was developed from a hit in a high-throughput screening campaign. Lead identification efforts produced biphenyl-4-carboxylic acid derivative (R)-22, which displayed a robust secretion of PYY after oral administration in a degree that can be correlated with the unbound plasma concentration. Further optimisation work focusing on reduction of the lipophilicity provided the 1-phenylpiperidine-4-carboxylic acid derivative (R)-29 (RO5527239), which showed an improved secretion of PYY and GLP-1, translating into a significant reduction of postprandial blood glucose excursion in an oral glucose tolerance test in DIO mice.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0960-894XeISSN: 1464-3405DOI: 10.1016/j.bmcl.2013.06.017Titel-ID: cdi_proquest_miscellaneous_1500758132
- Format
- –
- Schlagworte
- Administration, Oral, agonists, Animals, blood glucose, Blood Glucose - drug effects, Chemical probe, Drug Discovery, GLP-1, glucagon-like peptide 1, glucose tolerance tests, GPBAR1, hydrophobicity, Inhibitory Concentration 50, Mice, Molecular Structure, oral administration, Oximes - chemical synthesis, Oximes - chemistry, Oximes - pharmacology, Propane - analogs & derivatives, Propane - blood, Propane - chemical synthesis, Propane - chemistry, Propane - pharmacology, PYY, Receptors, G-Protein-Coupled - agonists, screening, secretion, TGR5