Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes,a new class of orally active GPBAR1 (TGR5) agonists |
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| Authors: | Henrietta Dehmlow Rubén Alvarez Sánchez Stephan Bachmann Caterina Bissantz Fritz Bliss Karin Conde-Knape Martin Graf Rainer E Martin Ulrike Obst Sander Susanne Raab Hans GF Richter Sabine Sewing Urs Sprecher Christoph Ullmer Patrizio Mattei |
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| Institution: | 1. Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland;2. Non-Clinical Safety, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland;3. Cardiovascular & Metabolism DTA, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland |
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| 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. |
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| Keywords: | GPBAR1 TGR5 PYY GLP-1 Chemical probe |
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