Event Information
4-Fluoro-2-cyanopyrrolidine Inhibitors of DPP-IV
- Abstract:
- Curt D. Haffner1, Darryl L. McDougald1, Steven M. Reister1, Kate Dwornik1, Sab Randhawa1, Brian Thompson1, David Cowan1, Brad Henke1, Richard Caldwell1, Istvan Kaldor1, James M. Lenhard2, Dallas Croom2, Daphne Clancy2, Donovon McConn3, Kevin M. Hedeen3, Kevin J. Wells-Knecht3, Melissa Secosky4, Wenhai Zhang4, (1) MV CEDD Chemistry Department, GlaxoSmithKline, P.O. Box 13398, Five Moore Drive, Research Triangle Park, NC 27709, curt.d.haffner@gsk.com, (2) Metabolic Diseases, (3) MV CEDD DMPK, (4) Assay Development & Compound Profiling Discovery Research.
Dipeptidyl peptidase IV (DPP-IV) also known as T-cell antigen CD26, first identified in 1966, is a widely expressed serine exopeptidase. It has been shown to have several functions in humans. First, it contributes to extracellular matrix binding, second it functions as an adenosine deaminase (ADA)-binding protein, and third exhibits post proline or alanine cleaving properties from oligo or polypeptides at the N-terminus. Incretins such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypepetide (GIP) have been shown to be inactivated by DPP-IV. Both of these incretins play a major role in glucose homeostasis. GLP-1 agonists are currently being progressed clinically and have shown antidiabetic efficacy, however due to their large peptide structures cannot be administered orally. Recently, orally bioavailable small molecule DPP-IV inhibitors have shown clinical efficacy in type II diabetic patients. We describe the synthesis and biological evaluation of a series of potent, selective and orally active DPP-IV inhibitors containing a 4-fluoro-2-cyanopyrrolidine nucleus.
Host: Eric Toone
Departmental Seminar