Synthesis, SAR and evaluation of C-aryl glucosides as sodium-glucose cotransporter inhibitors for the treatment of type 2 diabetes

MEDI 57

Wei Meng, wei.meng@bms.com1, William N. Washburn, washburw@bms.com1, Bruce A. Ellsworth, bruce.ellsworth@bms.com1, Ravindar N. Girotra1, Peggy J. McCann1, Prashant P. Deshpande, prashant.deshpande@bms.com2, Annie J. Pullockaran2, Manorama Patel1, Philip M. Sher1, Gang Wu1, Scott A. Biller, scott.biller@bms.com1, Deborah L. Hagan3, Songping Han3, Ashish Khanna4, Joseph R. Taylor3, Li Xin3, John R. Wetterau3, and Jean M. Whaley3. (1) Metabolic Diseases Chemistry, Bristol-Myers Squibb, Research and Development, Princeton, NJ 08543, (2) Process R & D, Bristol-Myers Squibb, Princeton, NJ 08543, (3) Metabolic Research Department, Bristol-Myers Squibb, Research and Development, Princeton, NJ 08534, (4) Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Research and Development, Princeton, NJ 08543
Diabetes mellitus is a chronic disease which is estimated to affect more than 171 million people worldwide. Poor HbA1c control in type 2 diabetic patients currently continues to stimulate the discovery and development of novel therapeutic agents. One such approach is the inhibition of the renal sodium-glucose co-transporters (SGLT2). Although several O-aryl glucosides, including the natural product phlorizin, have been shown to improve hyperglycemia in diabetic animal models, efficacy appeared to be limited by metabolic instability due to b-glucosidase activity. To address this issue, we replaced the oxygen linkage between the glucose and aglycone moieties with a carbon linkage, which led to metabolically stable SGLT2 inhibitors and culminated in the discovery of the clinical candidate dapagliflozin (BMS-512148). SAR for substitution of the aglycone central and distal aryl rings, synthetic methods, and the in vitro and in vivo profiles of select compounds will be described.

 

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

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Medicinal Chemistry

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