C-Aryl glucosides substituted at the 4′-position as potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 15; pp. 4465 - 4470
• Main Authors: Xu, Baihua, Feng, Yan, Cheng, Huawei, Song, Yanli, Lv, Binhua, Wu, Yuelin, Wang, Congna, Li, Shengbin, Xu, Min, Du, Jiyan, Peng, Kun, Dong, Jiajia, Zhang, Wenbin, Zhang, Ting, Zhu, Liangcheng, Ding, Haifeng, Sheng, Zelin, Welihinda, Ajith, Roberge, Jacques Y., Seed, Brian, Chen, Yuanwei
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.08.2011; Elsevier
• Subjects: Biological and medical sciences; C-Aryl glucosides; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; General and cellular metabolism. Vitamins; glucose; glucosides; Glucosides - chemical synthesis; Glucosides - chemistry; Glucosides - therapeutic use; Glucosuria; Humans; hydrophilicity; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - therapeutic use; Medical sciences; noninsulin-dependent diabetes mellitus; Pharmacology. Drug treatments; SGLT2; Sodium-dependent glucose co-transporter; Sodium-Glucose Transporter 1 - antagonists & inhibitors; Sodium-Glucose Transporter 1 - metabolism; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Sodium-Glucose Transporter 2 - metabolism; Structure-Activity Relationship; Type 2 diabetes mellitus; Glucosuria; Sodium-dependent glucose co-transporter; Diabetes; Type 2 diabetes mellitus; C-Aryl glucosides; SGLT2; Type 2 diabetes; Rat; Biological transport; Selectivity; Glucose; SGLT2 inhibitor; Kidney; Hypoglycemic agent; Structure activity relation; Chlorine Organic compounds; Sodium ion; Inhibition; C-Glycoside; Chemical synthesis; Human; Rodentia; Benzene derivatives; Elimination; Oral administration; Coupled transport; In vitro; In vivo; Vertebrata; Mammalia; Animal
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.06.032

A series of C-aryl glucosides with various substituents at the 4′-position of the distal aryl ring have been synthesized and evaluated for inhibition of hSGLT1 and hSGLT2. A series of C-aryl glucosides with various substituents at the 4′-position of the distal aryl ring have been synthesized and evaluated for inhibition of hSGLT1 and hSGLT2. Introduction of alkyl or alkoxy substituents at the 4′-position was found to improve SGLT2 potency, whereas introduction of a hydrophilic group at this position was deleterious. Compounds with alkoxy-, cycloalkoxy- or cycloalkenyloxy-ethoxy scaffolds exhibited good inhibitory activity and high selectivity toward SGLT2. Selected compounds were investigated for in vivo efficacy.