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Bioorg Med Chem Lett. 2013 Aug 15;23(16):4627-32. doi: 10.1016/j.bmcl.2013.06.017. Epub 2013 Jun 19.

Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists.

Author information

  • 1Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland.

Abstract

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.

KEYWORDS:

Chemical probe; GLP-1; GPBAR1; PYY; TGR5

PMID:
23831134
DOI:
10.1016/j.bmcl.2013.06.017
[PubMed - indexed for MEDLINE]
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