title: Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus.
abstract: Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC(50) of 70 nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50 mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin (300 mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bioavailability and moderate elimination in preclinical species.
authors.affiliation: Yuhan Research Institute, 416-1, Gongse-dong, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea. kaapjoo@yuhan.co.kr
authors.forename: Kaapjoo
authors.initials: K
authors.lastname: Park
authors.forename: Byoung Moon
authors.initials: BM
authors.lastname: Lee
authors.forename: Young Hwan
authors.initials: YH
authors.lastname: Kim
authors.forename: Taedong
authors.initials: T
authors.lastname: Han
authors.forename: Wonhui
authors.initials: W
authors.lastname: Yi
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Lee
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Choi
authors.forename: Wonee
authors.initials: W
authors.lastname: Chong
authors.forename: Chun Ho
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D015394:Molecular Structure; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D007004:Hypoglycemic Agents; D010627:Phenethylamines; D011725:Pyridines; C581883:YH-GKA; C037689:benzamide; D005941:Glucokinase