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

作者：Dehmlow Henrietta; Sanchez Ruben Alvarez; Bachmann Stephan; Bissantz Caterina; Bliss Fritz; Conde Knape Karin; Graf Martin; Martin Rainer E; Sander Ulrike Obst; Raab Susanne; Richter Hans G F; Sewing Sabine; Sprecher Urs; Ullmer Christoph; Mattei Patrizio^*

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(16): 4627-4632.

DOI：10.1016/j.bmcl.2013.06.017

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

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.

• 出版日期2013-8-15