title: A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agen.
abstract: Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin-secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue. DSC108 increased the intracellular Ca2+ level in MIN6-K8 cells. Competitive inhibition experiment and electrophysiological analysis revealed sulfonylurea receptor 1 (SUR1) to be the target of DSC108 and that this diphenylthiosemicarbazide directly inhibits ATP-sensitive K+ (KATP) channels. Pharmacokinetic analysis showed that DSC108 has a short half-life in vivo. Oral administration of DSC108 significantly suppressed the rises in blood glucose levels after glucose load in wild-type mice and improved glucose tolerance in the Goto-Kakizaki (GK) rat, a model of type 2 diabetes with impaired insulin secretion. Our data indicate that DSC108 is a novel insulin secretagogue, and is a lead compound for development of a new anti-diabetic agent.
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.|Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugawara
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Honda
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Reien
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Norihide
authors.initials: N
authors.lastname: Yokoi
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Seki
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Minami
authors.affiliation: Division of Advance Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Mori
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
authors.affiliation: Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
mesh_terms: D000284:Administration, Oral; D000598:Amino Acids, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology; D005951:Glucose Tolerance Test; D005905:Glyburide / Q000494:pharmacology / Q000627:therapeutic use; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D051381:Rats; D012663:Semicarbazides / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D064233:Sulfonylurea Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D013882:Thiosemicarbazones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000598:Amino Acids, Cyclic; D001786:Blood Glucose; C000620233:DSC108; D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D012663:Semicarbazides; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D013882:Thiosemicarbazones; D005905:Glyburide; D002118:Calcium