Synthesis and characterization of dapagliflozin, a potent selective SGLT2 inhibitor for treatment of diabetes

MEDI 28

William N. Washburn, washburw@bms.com1, Wei Meng, wei.meng@bms.com1, Bruce A. Ellsworth, bruce.ellsworth@bms.com1, Alexandra Nirschl2, Peggy J. McCann1, Manorama Patel1, Ravindar N. Girotra1, Gang Wu1, Philip M. Sher1, Scott A. Biller, scott.biller@bms.com1, Prashant P. Deshpande, prashant.deshpande@bms.com3, Deborah L. Hagan4, Joseph R. Taylor4, Mary Obermeier5, William G. Humphreys6, Ashish Khanna7, James G. Robertson8, Aiying Wang8, Song Ping Han8, John R. Wetterau4, Evan Janovitz7, Oliver Flint9, and Jean M. Whaley4. (1) Metabolic Diseases Chemistry, Bristol-Myers Squibb, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, (2) Discovery Chemistry, Bristol-Myers Squibb Company, P. O. Box 5400, Princeton, NJ 08543-5400, (3) Process R & D, Bristol-Myers Squibb, Princeton, NJ 08543, (4) Metabolic Research Department, Bristol-Myers Squibb, Research and Development, Princeton, NJ 08534, (5) Metabolism and Pharmacokinetics Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-5400, (6) Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, (7) Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Research and Development, Princeton, NJ 08543, (8) Department of Metabolic Research, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543-5400, (9) Drug Safety Evaluation, Bristol-Myers Squibb Company, P. O. Box 5400, Princeton, NJ 08543-5400
The synthesis and characterization of the first example of a C-aryl glucoside-derived renal sodium-dependent glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, are described. The clinical candidate dapagliflozin is a potent SGLT2 inhibitor (IC50 = 1 nM) exhibiting 1100-fold selectivity vs SGLT1, as well as high selectivity vs the facilitative transporters GLUT 1 and 4. Its absorption, distribution, metabolism, and excretion profile is favorable: following oral gavage of rats, 84% bioavailability with Cmax achieved in 100 minutes; low clearance rate of 4.8 mL/min/kg; elimination t½ after intravenous administration was 4.6 hours in rats, and 7.4 hours and 3.0 hours in dogs and monkeys, respectively. Oral administration of 0.1 mg/kg of dapagliflozin to normal or diabetic rats produced copious glucosuria unaccompanied by hypoglycemia. Plasma glucose levels of fed streptozotocin-induced diabetic Sprague-Dawley rats were reduced from 500 mg/dL to 200 mg/dL over a 5-hour period following oral administration of 0.1 mg/kg of dapagliflozin.
 

General Oral Session
1:30 PM-4:50 PM, Sunday, August 19, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

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