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Discovery of trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: structure-activity relationships, lead optimization, and chronic in vivo efficacy
- Source :
- Journal of medicinal chemistry. 57(8)
- Publication Year :
- 2014
-
Abstract
- Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.
- Subjects :
- Agonist
Male
medicine.medical_specialty
medicine.drug_class
Administration, Oral
Biological Availability
Mice, Obese
Pharmacology
Piperazines
Receptors, G-Protein-Coupled
Mice
Structure-Activity Relationship
In vivo
Glucagon-Like Peptide 1
Diabetes mellitus
Internal medicine
Drug Discovery
medicine
Animals
Humans
Hypoglycemic Agents
Receptor
G protein-coupled receptor
Drug discovery
Chemistry
medicine.disease
Glucagon-like peptide-1
G protein-coupled bile acid receptor
Mice, Inbred C57BL
Endocrinology
Molecular Medicine
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 57
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....3f51c6edd6563cb2004b9b410744938c