title: Novel GPR119 agonist HD0471042 attenuated type 2 diabetes mellitus.
abstract: In type 2 diabetes mellitus (T2DM) patients, the gradual loss of pancreatic β-cell function is a characteristic feature of disease progression that is associated with sustained hyperglycemia. Recently, G protein-coupled receptor 119 (GPR119) has been identified as a promising anti-diabetic therapeutic target. It is predominantly expressed in pancreatic β-cells, directly promotes glucose stimulated insulin secretion and indirectly increases glucagon-like peptide 1 (GLP-1) levels reducing appetite and food intake. Activation of GPR119 leads to insulin release in β-cells by increasing intracellular cAMP. Here, we identified a novel structural class of small-molecule GPR119 agonists, HD0471042, consisting of substituted a 3-isopropyl-1,2,4-oxadiazol-piperidine derivative with promising potential for the treatment of T2DM. The GPR119 agonist, HD0471042 increased intracellular cAMP levels in stably human GPR119 expressing CHO cell lines and HIT-T15 cell lines, hamster β-cell line expressing endogenously GPR119. HD0471042, significantly elevated insulin release in INS-1 cells of rat pancreatic β-cell line. In in vivo experiments, a single dose of HD0471042 improved glucose tolerance. Insulin and GLP-1 level were increased in a dose-dependent manner. Treatment with HD0471042 for 6 weeks in diet induced obesity mice and for 4 weeks in ob/ob and db/db mice improved glycemic control and also reduced weight gain in a dose-dependent manner. These data demonstrate that the novel GPR119 agonist, HD0471042, not only effectively controlled glucose levels, but also had an anti-obesity effect, a feature observed with GLP-1. We therefore suggest that HD0471042 represents a new type of anti-diabetes agent with anti-obesity potential for the effective treatment of type 2 diabetes.
authors.affiliation: New Drug Discovery Laboratory, Hyundai Pharmaceutical Co. Ltd., Gyeong-Gi Bio-Center, Lui-dong, Yeongtong-gu, Suwon, Gyeonggi-do, South Korea.
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Ha
authors.forename: Young-Seok
authors.initials: YS
authors.lastname: Kim
authors.forename: Chun Hwa
authors.initials: CH
authors.lastname: Kim
authors.forename: Hyo-Sun
authors.initials: HS
authors.lastname: Choi
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Park
authors.forename: Dae Hoon
authors.initials: DH
authors.lastname: Kim
authors.forename: Jae-Keol
authors.initials: JK
authors.lastname: Rhee
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection; D015430:Weight Gain / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; C519854:GPR119 protein, human; C532423:GPR119 protein, rat; C516207:Gpr119 protein, mouse; C000594173:HD0471042; D007004:Hypoglycemic Agents; D007328:Insulin; D010069:Oxadiazoles; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP