title: High-throughput screening for GPR119 modulators identifies a novel compound with anti-diabetic efficacy in db/db mice.
abstract: G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic β cells and enteroendocrine cells. It is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, thereby representing a promising target for the treatment of type 2 diabetes. Although a number of GPR119 agonists were developed, no positive allosteric modulator (PAM) to this receptor has been reported. Here we describe a high-throughput assay for screening GPR119 PAMs and agonists simultaneously. Following screening of a small molecule compound library containing 312,000 synthetic and natural product-derived samples, one potent GPR119 agonist with novel chemical structure, MW1219, was identified. Exposure of MIN6 and GLUTag cells to MW1219 enhanced glucose-stimulated insulin secretion and GLP-1 release; once-daily oral dosing of MW1219 for 6 weeks in diabetic db/db mice reduced hemoglobin A1c (HbA1c) and improved plasma glucose, insulin and GLP-1 levels; it also increased glucose tolerance. The results demonstrate that MW1219 is capable of effectively controlling blood glucose level and may have the potential to be developed as a new class of anti-diabetic agents.
authors.affiliation: The National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhao
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Dehua
authors.initials: D
authors.lastname: Yang
authors.forename: Olivier
authors.initials: O
authors.lastname: Nosjean
authors.forename: Jean
authors.initials: J
authors.lastname: Boutin
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism
chemical_list: C521085:AR 231453; C519854:GPR119 protein, human; C516207:Gpr119 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D010069:Oxadiazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1