ORGN 230 |
| Dipeptidyl peptidase IV (DPP-4), a member of a family of proline selective serine dipeptidases, is responsible for the N-terminal inactivation of GLP-1 and GIP, incretin hormones that evoke glucose dependent secretion of insulin and inhibition of glucagon release. Inhibitors of DPP-4 have been shown to increase circulating levels of GLP-1 and GIP, both in animal models and in the clinic, resulting in improved glucose tolerance. Thus, DPP-4 inhibitors represent a potential new therapy for type 2 diabetes. Early α-amino acid-derived DPP-4 inhibitors that were not selective over related family members, in particular DPP8 and DPP9, induced profound toxicities in preclinical species. SAR studies on two novel screening hits provided a series of β-amino acid-derived inhibitors that were highly selective over these enzymes. Optimization of this series led to the discovery of JANUVIA™ (sitagliptin), a selective DPP-4 inhibitor which was recently approved by the FDA for the treatment of type 2 diabetes. |
|
Herbert C. Brown Award for Creative Research in Synthetic Methods: Symposium in Honor of David A. Evans
8:30 AM-12:00 PM, Monday, March 26, 2007 McCormick Place Lakeside -- Room E450 A/B, Level 4, Oral
Division of Organic Chemistry |