Dipeptidyl peptidase IV inhibitors incorporating fused azoles as effective amide isosteres

MEDI 60

Hong Dong, hong_dong@merck.com1, Wallace T. Ashton, wally_ashton@merck.com1, Rosemary M. Sisco1, Kathryn A. Lyons1, Huaibing He1, Barbara Leiting2, Reshma A. Patel2, Joseph K. Wu2, Xiaoping Zhang2, Nancy A. Thornberry2, and Ann E. Weber1. (1) Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, (2) Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065
Therapies based on glucagon-like peptide 1 (GLP-1), an incretin hormone that stimulates glucose-dependent insulin biosynthesis and secretion, have emerged as one of the most promising areas in diabetes research. GLP-1 lacks oral activity and is rapidly degraded by dipeptidyl peptidase IV (DPP-4). Inhibition of DPP-4 promotes sustained elevation of endogenous GLP-1 levels, in a glucose-dependent manner, thus improving glucose tolerance with minimal risk of hypoglycemia. Previous work from these laboratories showed that appropriately substituted γ-aryl-β-aminoacyl derivatives of ring-fused piperazines and piperidines are potent, selective, and orally bioavailable inhibitors of DPP-4. We now report the synthesis and biological evaluation of analogous compounds in which the amide moiety was replaced by a fused triazole or imidazole. The effect of ring size, substitution pattern, and fused ring number was investigated. The potency at DPP-4 and selectivity versus other DASH proteins along with the rat pharmacokinetic properties of key compounds will be presented.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007