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

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

  • Bioorg Med Chem Lett. 2013 Aug 15;23(16):4627-32. doi: 10.1016/j.bmcl.2013.06.017.
Henrietta Dehmlow 1,  Rubén Alvarez Sánchez,  Stephan Bachmann,  Caterina Bissantz,  Fritz Bliss,  Karin Conde-Knape,  Martin Graf,  Rainer E Martin,  Ulrike Obst Sander,  Susanne Raab,  Hans G F Richter,  Sabine Sewing,  Urs Sprecher,  Christoph Ullmer,  Patrizio Mattei
Affiliations

Affiliation

  • 1 Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland.
PMID: 23831134 DOI: 10.1016/j.bmcl.2013.06.017
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.

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