Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists.
Bioorg Med Chem Lett
; 23(16): 4627-32, 2013 Aug 15.
Article
in En
| MEDLINE
| ID: mdl-23831134
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oximes
/
Propane
/
Blood Glucose
/
Receptors, G-Protein-Coupled
/
Drug Discovery
Limits:
Animals
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2013
Document type:
Article
Affiliation country: