Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1370967 | Bioorganic & Medicinal Chemistry Letters | 2011 | 7 Pages |
The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure–activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.
Graphical abstractThe lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold led to the identification of compound 36j as a potent and orally active GPR119 agonist with high agonist activity.Figure optionsDownload full-size imageDownload as PowerPoint slide