C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 5; pp. 1569 - 1572
• Main Authors: Robinson, Ralph P., Mascitti, Vincent, Boustany-Kari, Carine M., Carr, Christopher L., Foley, Patrick M., Kimoto, Emi, Leininger, Michael T., Lowe, Andre, Klenotic, Michelle K., MacDonald, James I., Maguire, Robert J., Masterson, Victoria M., Maurer, Tristan S., Miao, Zhuang, Patel, Jigna D., Préville, Cathy, Reese, Matthew R., She, Li, Steppan, Claire M., Thuma, Benjamin A., Zhu, Tong
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.03.2010; Elsevier
• Subjects: Animals; Biological and medical sciences; C-Aryl glycoside; Cyclization; Diabetes; General and cellular metabolism. Vitamins; Glucose; Glycosides - chemical synthesis; Glycosides - chemistry; Glycosides - pharmacokinetics; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Inhibitor; Male; Medical sciences; Microsomes, Liver - metabolism; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; SGLT; SGLT2; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Sodium-Glucose Transporter 2 - metabolism; Spiro Compounds - chemistry; Transporter; SGLT2; C-Aryl glycoside; SGLT; Inhibitor; Glucose; Diabetes; Transporter; Endocrinopathy; Rat; Dapagliflozin; Biological transport; Kidney; Sodium ion; C-Glycoside; Chemical synthesis; Aldose; Diabetes mellitus; Rodentia; Oral administration; Coupled transport; Bioavailability; Biological activity; Spiran; Vertebrata; Mammalia; Animal; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.01.075

Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.