title: Modification on the O-glucoside of Sergliflozin-A: A new strategy for SGLT2 inhibitor design.
abstract: Poor pharmacokinetic stability is one of the issues of O-glucoside SGLT2 inhibitors in clinical trials, hence C-glucoside inhibitors have been developed and extensively applied. Herein, we provided an alternative approach to improve the pharmacokinetic stability of such inhibitors. Nine derivatives of Sergliflozin-A with modifications on the O-glucoside fragment were prepared, among which the 4-O-methyl derivative exhibited similar pharmacodynamics potency in excreted glucose urine test. Most attractively, significantly increased pharmacokinetic stability was observed for 4-O-methyl derivative of O-glucosides. This work proved that modification on the O-glucoside fragment could be a promising approach to the future SGLT2 inhibitor design.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China.
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China.
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China. Electronic address: pwang@nankai.edu.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China. Electronic address: jieshen@nankai.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000652:urine; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000652:urine; D066298:In Vitro Techniques; D009005:Monosaccharides / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: C000621250:2-((4-methoxyphenyl)methyl)phenyl-4-O-methyl-beta-D-glucopyranoside; D001559:Benzhydryl Compounds; D007004:Hypoglycemic Agents; D009005:Monosaccharides; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C000621249:sergliflozin-A
keywords: O-Glucoside; Pharmacokinetic stability; SGLT2 inhibitor; Sergliflozin-A