ORGN 212 |
| Emma R. Parmee1, Jiafang He2, Anthony Mastracchio1, Scott D. Edmondson1, Jinyou Xu3, Lawrence F. Colwell Jr.3, Michael H. Fisher4, Bahanu Habulihaz3, Huaibing He2, Barbara Leiting5, Kathryn A. Lyons2, Frank Marsilio6, Reshma A. Patel6, Joseph K. Wu7, Mathew J. Wyvratt8, Nancy A. Thornberry9, and Ann E. Weber8. (1) Department of Basic Chemistry, Merck & Co, PO Box 2000, Rahway, NJ 07065, (2) Department of Medicinal Chemistry, Merck & Co. Inc, PO Box 2000, Rahway, NJ 07065, (3) Department of Medicinal Chemistry, Merck & Co., Inc, P.O.Box 2000, Rahway, NJ 07065, (4) Department of Medicinal Chemistry, Merck Research Labs, P.O.Box 2000, Rahway, NJ 07065, (5) Department of Metabolic Disorders, Merck & Co., Inc, P.O. Box 2000, Rahway, NJ 07065, (6) Department of Metabolic Disorders, Merck & Co. Inc, PO Box 2000, Rahway, NJ 07065-0900, (7) Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, (8) Department of Medicinal Chemistry, Merck Research Laboratories, P.O.Box 2000, Rahway, NJ 07065, (9) Department of Metabolic Disorders, Merck & Co, PO Box 2000, Rahway, NJ 07065-0900 |
| Inhibition of dipeptidyl peptidase IV (DP-IV), a proline specific serine dipeptidase, is a novel therapeutic approach to the treatment of type 2 diabetes. Evidence for this has been obtained with DP-IV deficient mice and also in human clinical trials with small molecule inhibitors. DP-IV inhibitors act, in part, as indirect stimulators of insulin secretion by stabilization of the incretin hormone glucagon-like peptide 1 (GLP-1). In contrast to many current therapies, this mechanism carries with it a low risk of hypoglycemia as GLP1 only stimulates insulin release in response to elevated plasma glucose levels. Herein, we would like to report the synthesis and biological activity of a novel series of DP-IV inhibitors, which do not possess an electrophilic nitrile. Optimized compounds were low nanomolar inhibitors of the enzyme with excellent selectivity and pharmacokinetic profiles. |
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Women in Organic Synthesis
8:45 AM-12:00 PM, Monday, August 23, 2004 Pennsylvania Convention Center -- Ballroom A, Oral
Division of Organic Chemistry |