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

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.

DOI: 10.1016/j.bmcl.2013.06.017

Cite this paper

@article{Dehmlow2013DiscoveryAO, title={Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists.}, author={Henrietta Dehmlow and Rub{\'e}n Alvarez S{\'a}nchez and Stephan Bachmann and Caterina Bissantz and Fritz Bliss and Karin Conde-Knape and Martin W. Graf and Rainer E. Martin and Ulrike Obst Sander and Susanne Raab and Hans G F Richter and Sabine Sewing and Urs Sprecher and Christoph Ullmer and Patrizio Mattei}, journal={Bioorganic & medicinal chemistry letters}, year={2013}, volume={23 16}, pages={4627-32} }