title: 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.
authors.affiliation: Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland.
authors.forename: Henrietta
authors.initials: H
authors.lastname: Dehmlow
authors.forename: Rubén
authors.initials: R
authors.lastname: Alvarez Sánchez
authors.forename: Stephan
authors.initials: S
authors.lastname: Bachmann
authors.forename: Caterina
authors.initials: C
authors.lastname: Bissantz
authors.forename: Fritz
authors.initials: F
authors.lastname: Bliss
authors.forename: Karin
authors.initials: K
authors.lastname: Conde-Knape
authors.forename: Martin
authors.initials: M
authors.lastname: Graf
authors.forename: Rainer E
authors.initials: RE
authors.lastname: Martin
authors.forename: Ulrike
authors.initials: U
authors.lastname: Obst Sander
authors.forename: Susanne
authors.initials: S
authors.lastname: Raab
authors.forename: Hans G F
authors.initials: HG
authors.lastname: Richter
authors.forename: Sabine
authors.initials: S
authors.lastname: Sewing
authors.forename: Urs
authors.initials: U
authors.lastname: Sprecher
authors.forename: Christoph
authors.initials: C
authors.lastname: Ullmer
authors.forename: Patrizio
authors.initials: P
authors.lastname: Mattei
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: D001786:Blood Glucose; D010091:Oximes; D043562:Receptors, G-Protein-Coupled; D011407:Propane; C014513:1,3-diphenylpropane
keywords: Chemical probe; GLP-1; GPBAR1; PYY; TGR5